Methods for treating inflammatory skin conditions

ABSTRACT

The present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein said administration provides an effective plasma or interstitial fluid concentration of minocycline for treating the inflammatory skin condition.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/241,754 filed on Jan. 7, 2019, which claims priority from IndianPatent Application No. IN 201741023993 filed on Jan. 7, 2018, the entiredisclosures of which is incorporated herein by this reference.

TECHNICAL FIELD

The present application relates to a method of treating an inflammatoryskin condition by administering a pharmaceutical composition comprisinga reduced dose of minocycline to a subject in need thereof, wherein saidadministration provides an effective plasma or interstitial fluidconcentration of minocycline for treating said inflammatory skincondition.

BACKGROUND

Inflammatory skin conditions are those conditions of the skin in whichinflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes)infiltrate the skin with no overt or known infectious etiology. Symptomsof inflammatory skin conditions generally include erythema (redness),edema (swelling), pain, pruritus, increased surface temperature and lossof function.

Rosacea is one such an inflammatory disorder of the skin which ischaracterized by inflammatory lesions of the skin that may resemble acnevulgaris papules and pustules (“acneform” lesions). It is a disorder ofthe superficial cutaneous vasculature resulting in erythema, accentuatedflushing and telangiectasia and occurs predominantly in middle-agedadults and is virtually never observed in adolescents or young adults.Overall, rosacea is a type of inflammation that shows up as a rash,similar to other rashes/breakouts that cause an area of red, sensitiveand inflamed skin. Such rashes are caused by irritation, allergies,infections, underlying diseases and structural defects of the skin,including blocked pores or malfunctioning oil glands. With time, peoplewho have rosacea often see permanent redness in the center of theirface. Rosacea related symptoms include, papules, pustules, blackheads,whiteheads or milia, nodules and cysts.

There are actually four different types of rosacea, although some peoplewill have symptoms from more than one type at a time. The four types ofrosacea are:

-   -   1. Erythematotelangiectatic rosacea: Redness, flushing, visible        blood vessels,    -   2. Papulopustular rosacea: Redness, swelling, and acne-like        breakouts,    -   3. Phymatous rosacea: Skin thickens and has a bumpy texture,        redness and various symptoms from other subtypes, and    -   4. Ocular rosacea: Eyes red and irritated, eyelids can be        swollen, and person may have what looks like a sty.

There are several subtypes of rosacea including, for example, but notlimited to, pyoderma faciale (also known as rosacea fulminans), rosaceaconglobate or phymatous rosacea.

Thus, a rosacea related disorder is any disorder which can occur inparallel with rosacea or be a contributing factor to the outbreak ofrosacea or can resemble rosacea. Perioral dermatitis is an erythematous,papulopustular facial eruption that resembles rosacea and/or acne buttypically starts around the nose.

Rosacea is a chronic inflammatory disorder characterized by facialflushing, telangiectasias, erythema, papules, pustules, and in severecases, rhinophyma. Rosacea can be associated with the elevated levels ofcathelicidins or with the elevated levels of a stratum corneum trypticenzyme (SCTE). Rosacea includes any of the known types or subtypesclassified in the art.

Acne is another such inflammatory disorder of the skin which ischaracterized by various types of lesions. The lesions associated withacne are usually categorized as either non-inflammatory or inflammatory.The spectrum of acne lesions ranges from non-inflammatory open or closedcomedones; mild inflammatory acne lesions with comedones and few papulesand pustules; moderate inflammatory acne lesions with comedones; severalpapules and pustules, and few nodules; or severe inflammatory acnelesions with comedones, several papules and pustules, multiple nodules,and scarring.

There are various treatment options available for inflammatory skinconditions like rosacea. It is treated with a variety of topical and/ortherapies including topical and oral antibiotics, sodium sulfacetamide,and metronidazole.

Topical azelaic acid is an alternative to topical antibiotics to treatmild-to-moderate spots. However, some people find that it can causeside-effects such as burning, stinging, itching, scaling and dry skin.

When antibiotics are ineffective or poorly tolerated, oral isotretinoinmay be effective, however, it has various side effects which is notsuitable for everyone. Ivermectin cream is used occasionally for peoplewith rosacea. It works by killing the mite Demodex folliculorum and alsoworks to reduce some of the inflammation in the skin. Brimonidine gel isused to treat facial redness. It results in short-term vasoconstrictionbut has no effects on telangiectasia. Certain medications such asclonidine (an alpha2-receptor agonist) may reduce the vasculardilatation (widening of blood vessels) that results in flushing. Oralnon-steroidal anti-inflammatory agents such as diclofenac may reduce thediscomfort and redness of affected skin. Calcineurin inhibitors such astacrolimus ointment and pimecrolimus cream are reported to help somesubjects with rosacea. Other than medications, persistent telangiectasiahas shown improvements with surgical treatments like vascular laser orintense pulsed light treatment. Papulopustular rosacea may also improvewith laser treatment or radiofrequency. Other treatments like cautery,diathermy (electrosurgery) or sclerotherapy (strong saline injections)may also be helpful. Nutraceuticals targeting flushing, facial rednessand inflammation may be beneficial.

Among various available treatment options, oral antibiotics likedoxycycline is preferred, which reduces inflammation significantly. Theyreduce the redness, papules, pustules and eye symptoms of rosacea. Theantibiotics are usually prescribed for 6 to 16 weeks, with the durationdepending on the severity of the rosacea. Further courses are oftenneeded from time to time, as the antibiotics don't cure the disorder.Sometimes other oral antibiotics such as cotrimoxazole or metronidazoleare prescribed for resistant cases. Anti-inflammatory effects ofantibiotics are under investigation and shown to inhibit matrixmetalloproteinases function and in turn reduce cathelicidins andinflammation.

Currently in the United States of America, oral doxycycline is marketedunder the brand name ORACEA®—40 mg once daily capsules—from GaldermaLaboratories, approved by the US FDA in 2006. ORACEA® is indicated forthe treatment of only inflammatory lesions (papules and pustules) ofrosacea in adults. However, ORACEA® has well-known esophageal irritationand ulceration related side effects that really bother the subjects.

“MINOCIN®” which is a capsule comprising 50 mg, 75 mg or 100 mg ofminocycline and approved for the treatment of various infections due tosusceptible strains.

The usage of minocycline in higher strengths is associated withvestibular deregulation related adverse events like vertigo,incoordination or light-headedness. There is a clear void in the area oftreating inflammatory skin conditions like rosacea in terms of safe andcommercially approved minocycline dosage forms. And there is no approveddosage form of minocycline available for treating inflammatory skinconditions like rosacea.

There is a clear unmet need in the arts to provide alternatives fortreatment for inflammatory skin conditions, which increase theopportunities for a greater number of individuals to achieve effectivetreatment. In this regard, there is a need for methods of providing aneffective dose of minocycline for treatment of inflammatory skinconditions that maximizes therapeutic effect, while managing the adverseeffects.

In other words, there is a need to provide minocycline dosage forms forbetter compliance to treat inflammatory skin conditions, which minimizethe fluctuation or variance between peak and trough plasma orinterstitial fluid levels of minocycline, with reduced side effects.

It is well known in the art that peak-to-trough fluctuations of drugconcentration critically affect clinical response, tolerability andultimately selection of appropriate drug and dosage forms required fortreatment of inflammatory skin conditions.

Accordingly, the present application relates to a method of treating aninflammatory skin condition such as rosacea by administering apharmaceutical composition comprising a reduced dose of minocyclinecomprising a therapeutically effective amount of minocycline to providedesired minocycline concentration in plasma and/ or interstitial fluidfor treating said inflammatory skin condition.

The present application provides a method of treating an inflammatoryskin condition such as rosacea by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to provide aneffective treatment for said inflammatory skin condition.

The present application provides a method of treating an inflammatoryskin condition such as acne by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to provide aneffective treatment for said inflammatory skin condition.

The present application also provides body-weight-independent dosingregimen for minocycline in a suitable pharmaceutical dosage formcomprising a reduced dose of minocycline, as compared to otherminocycline compositions for treating inflammatory skin conditions.

SUMMARY

In one embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering a compositioncomprising a reduced dose of minocycline.

In an aspect, the present application relates to a method of treating aninflammatory skin condition selected from, but not limited to, rosacea,acne, atopic dermatitis, folliculitis, perioral dermatitis,photo-damage, actinic keratosis, psoriasis, treatment of chronic wounds,bed sores, keratosis pilaris, surgical scars, acne scars, sebaceouscysts, inflammatory dermatoses, post inflammatory hyperpigmentation,xerosis, pruritis, lichen planus, nodular prurigo, eczema, and miliaria.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a reduced dose of minocycline.

In yet another embodiment, the present application relates to a methodof treating acne by administering a pharmaceutical compositioncomprising a reduced dose of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition of the present application comprises about 10 mg to 40 mg ofminocycline.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising an equivalent or a reduced dose ofminocycline as compared to an oral doxycycline composition comprising 40mg of doxycycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising an equivalent or a reduced dose of minocycline as compared toan oral doxycycline composition comprising 40 mg of doxycycline.

In another embodiment, the present application relates to a method oftreating acne by administering a pharmaceutical composition comprisingan equivalent or a reduced dose of minocycline as compared to an oraldoxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition byadministering an oral pharmaceutical composition comprising about 10 mgto 40 mg of minocycline to a subject in need thereof, wherein saidadministration results in an equivalent or improved efficacy as comparedto an oral doxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering an oralpharmaceutical composition comprising about 10 mg to 40 mg ofminocycline to a subject in need thereof, wherein said administrationresults in an equivalent or improved efficacy as compared to an oraldoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is effective or ineffective, andadministering oral pharmaceutical composition comprising an equivalentor a reduced dose of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising:

-   -   (a) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        ineffective, and administering oral pharmaceutical composition        comprising an equivalent or a reduced dose of minocycline; or    -   (b) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        effective, and administering oral pharmaceutical composition        comprising a reduced dose of minocycline.

In an aspect of the above embodiments, the composition of the presentapplication comprises about 10 mg, about 20 mg, about 30 mg, or about 40mg of minocycline.

In another aspect of the above embodiments, the method of treatingrosacea reduces the severity of rosacea as compared to the severity ofrosacea before the treatment, as assessed using Investigator's GlobalAssessment (IGA) scale.

In another aspect of the above embodiments, said method results inimproved efficacy as assessed by the IGA score, in at least about 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75% of thesubjects as compared to the IGA score before the treatment.

In another aspect of the above embodiments, said method reduces the IGAscore by at least about 25%, about 50%, about 75% or about 100% ascompared to the IGA score following administration of an oraldoxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, said method significantlyreduces the number of inflammatory lesions as compared to the number ofinflammatory lesions before the treatment.

In another aspect of the above embodiments, said method reduces thenumber of inflammatory lesions of the subject by at least about 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%,95% or 100% as compared to the number of inflammatory lesions before thetreatment.

In another aspect of the above embodiments, said method reduces thenumber of inflammatory lesions by at least about 15%, about 30%, about50% or about 75% as compared to the number of inflammatory lesionsfollowing administration of an oral doxycycline composition comprising40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less, exhibitsmaximum plasma concentration (C_(maxSSP)) of minocycline of not morethan about 500 ng/ml.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsfluctuation index (FI_(SSP)) of about 0.9 to about 1.3 in plasma.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsat least about a 30% lower fluctuation index (FI_(SSP))[(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma, as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsmaximum plasma concentration (C_(maxSSP)) of at least about 10% lower ascompared to oral administration of a doxycycline composition comprising40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsat least about a 10% reduction in coefficient of variance (CV %) ofmaximum plasma concentration (C_(maxSSP)) as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsat least about a 10% reduction in coefficient of variance (CV %) ofminocycline exposure (AUC_(0-tSSP)) in plasma as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsa plasma concentration ratio (C_(maxSSP): C_(maxP)) of at least about a30% lower ratio as compared to oral administration of a doxycyclinecomposition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsa plasma concentration ratio (C_(maxSSP): C_(maxP)) of at least about0.9.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less exhibitsan average plasma concentration (C_(avgSSP)) of at least about 20% loweras compared to oral administration of a doxycycline compositioncomprising 40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less, exhibitsratio of minocycline exposure in interstitial fluid to plasma(AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 10%, about 20%, about30%, about 40% or about 50% higher as compared to oral administration ofa doxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication upon oral administration for about 3 weeks or less, exhibitsratio of minocycline exposure in interstitial fluid to plasma ratio(AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 10%, about 20%, about30%, about 40% or about 50% higher as compared to oral administration ofa doxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the composition of presentapplication comprising about 10 mg to about 40 mg dose of minocycline,upon oral administration for about 3 weeks or less exhibits at least oneof the following pharmacokinetic parameters, when measured in plasmasamples:

-   -   (a) C_(maxSSP)/D of about 5 ng/ml/mg to about 12 ng/ml/mg; or    -   (b) AUC_(0-tSSP)/D of about 60 ng/ml/mg to about 114 ng/ml/mg.

In another aspect of the above embodiments, the composition of presentapplication comprising about 10 mg to about 40 mg dose of minocycline,upon oral administration exhibits at least one of the followingpharmacokinetic parameters, when measured in interstitial fluid samples:

-   -   (a) C_(maxIF)/D of about 1.8 ng/ml/mg to about 3 ng/ml/mg; or    -   (b) AUC_(0-tIF)/D of about 25 ng/ml/mg to about 40 ng/ml/mg.

In an embodiment, the present application relates to a method oftreating rosacea comprises administering a pharmaceutical compositioncomprising about 10 mg to about 40 mg of minocycline to a subject inneed thereof.

In an aspect of the above embodiments, the pharmaceutical composition ofpresent application is administered once daily.

In an aspect of the above embodiments, the pharmaceutical composition ofpresent application is administered twice daily.

In another aspect of the above embodiments, the pharmaceuticalcomposition of present application is with or without food.

In another aspect of the above embodiments, the pharmaceuticalcomposition of present application is prepared in the form of oraltablets, capsules, pills, minitablets, pellets, granules, powder,suspension or syrup.

In an embodiment, the present application relates to a method oftreating rosacea by administering oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said method provides body-weight-independent dosing regimen forminocycline.

In an embodiment, the present application relates to a method ofpreparing an oral pharmaceutical composition for treating aninflammatory skin condition in a subject in need thereof. In anembodiment, the method involves selecting and providing minocycline inthe composition at an equivalent or a reduced dose of minocycline, ascompared to an oral doxycycline composition comprising 40 mg ofdoxycycline. In an embodiment, the composition provides an equivalent orimproved efficacy as compared to the oral doxycycline compositioncomprising 40 mg of doxycycline.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show mean plasma concentration for ORACEA®, Example 1and Example 3 for day 1 and day 21 respectively, when subjected to anopen-label, 6-cohort pharmacokinetic study.

FIGS. 2A and 2B show mean interstitial fluid concentration for ORACEA®,Example 1 and Example 3 for day 1 and day 21 respectively, whensubjected to an open-label, 6-cohort pharmacokinetic study.

FIG. 3 shows IGA “treatment success” for Example 1, Example 3, ORACEA®and placebo, when subjected to a 16-week, multi-center, randomized,double-blind, parallel-group, controlled study.

FIG. 4 shows change in lesion nos. for papules, pustules and nodules forExample 1, Example 3, ORACEA® and placebo, when subjected to a 16-week,multi-center, randomized, double-blind, parallel-group, controlledstudy.

FIG. 5 shows change in total inflammatory lesions for Example 1, Example3, ORACEA® and placebo, when subjected to a 16-week, multi-center,randomized, double-blind, parallel-group, controlled study.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

The details of one or more embodiments of the present invention are setforth in this document. Modifications to embodiments described in thisdocument, and other embodiments, will be evident to those of ordinaryskill in the art after a study of the information provided in thisdocument. The information provided in this document, and particularlythe specific details of the described exemplary embodiments, is providedprimarily for clearness of understanding and no unnecessary limitationsare to be understood therefrom. In case of conflict, the specificationof this document, including definitions, will control.

Definitions: The terms as used herein have the following meanings:

The present invention can comprise or consist essentially of thecomponents of the present invention as well as other ingredients orelements described herein. As used herein, “comprising” means theelements recited, or their equivalent in structure or function, plus anyother element or elements which are not recited. The terms “having,”“including,” and “comprised of” are also to be construed as open endedunless the context suggests otherwise. As used herein, “consistingessentially of” means that the invention may include ingredients inaddition to those recited in the claim, but only if the additionalingredients do not materially alter the basic and novel characteristicsof the claimed invention. As used herein, “consisting of” means that theinvention excludes additional elements, steps, or ingredients notspecified in the claim.

The terms “a” and “the” as used herein, are understood to encompass theplural as well as the singular or otherwise clearly mentioned whereverneeded. For example, reference to “an excipient” includes reference toone or more of such excipients, and reference to “the vehicle” includesreference to one or more of such vehicles.

The terms “about,” “up to,” “generally,” and the like are to beconstrued as modifying a term or value such that it is not an absolute.Such terms will be defined by the circumstances and the terms that theymodify as those terms are understood by those of skilled in the art.This includes, at very least, the degree of expected experimental error,technical error and instrumental error for a given experiment, techniqueor an instrument used to measure a value.

The term “about” is used to provide flexibility to a numerical rangeendpoint by providing that a given value may be “a little above” or “alittle below” the endpoint. As an illustration, a numerical range of“about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.

The terms “composition” and “formulation” refer to a mixture of two ormore compounds, elements, or molecules. Also this term may be used torefer to a mixture of one or more active agents with a pharmaceuticallyacceptable vehicle or excipients. Furthermore, the term “dosage form”can include one or more formulation(s) or composition(s) provided in aformat for oral administration like tablets, capsules, pills,minitablets, pellets, granules, powder, suspension, syrup and the likeor mixtures thereof.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance does or does not occur orexist and that the description includes instances where said event orcircumstance occurs or exists, and instances where it does not.

As used herein, the terms “treatment” or “treating” that includes“alleviating,” relate to curing or substantially curing a condition, aswell as ameliorating at least one symptom of the condition, and areinclusive of prophylactic treatment and therapeutic treatment. As wouldbe recognized by one or ordinary skill in the art, treatment that isadministered prior to clinical manifestation of a condition then thetreatment is prophylactic (i.e., it protects the subject againstdeveloping the condition). If the treatment is administered aftermanifestation of the condition, the treatment is therapeutic (i.e., itis intended to diminish, ameliorate, control, alleviate or maintain theexisting condition and/or side effects associated with the condition).The terms relate to medical management of a subject with the intent tosubstantially cure, ameliorate, stabilize, or substantially prevent acondition, including but not limited to prophylactic treatment topreclude, avert, obviate, forestall, stop, or hinder something fromhappening, or reduce the severity of something happening, especially byadvance action. As such, the terms treatment or treating include, butare not limited to: inhibiting the progression of a condition ofinterest; arresting or preventing the development of a condition ofinterest; reducing the severity of a condition of interest; amelioratingor relieving symptoms associated with a condition of interest; causing aregression of the condition of interest or one or more of the symptomsassociated with the condition of interest; and preventing a condition ofinterest or the development of a condition of interest.

The term “minocycline” as used herein, is intended to include, but isnot limited to, minocycline, its pharmaceutically acceptable salts, andpharmaceutically acceptable, pharmacologically active derivatives ofminocycline, including both individual enantiomers of minocycline(dextrogyral and levogyral enantiomers) in their substantially pure formand their pharmaceutically acceptable salts, mixtures (in any ratio) ofminocycline enantiomers and their pharmaceutically acceptable salts, andactive metabolites of minocycline and their pharmaceutically acceptablesalts. The chemical name of minocycline is[4S-(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.The solid state form of minocycline can be used. Alternatively, forexample, minocycline can be amorphous or crystalline.

The term “doxycycline” as used herein, is intended to include, but isnot limited to, doxycycline, its pharmaceutically acceptable salts, andpharmaceutically acceptable, pharmacologically active derivatives ofdoxycycline, including both individual enantiomers of doxycycline intheir substantially pure form and their pharmaceutically acceptablesalts, mixtures (in any ratio) of doxycycline enantiomers and theirpharmaceutically acceptable salts, and active metabolites of doxycyclineand their pharmaceutically acceptable salts. The chemical name ofdoxycycline is(4S,4aR,5S,5aR,6R,12aR)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide.The solid state form of doxycycline can be used. Alternatively, forexample, doxycycline can be amorphous or crystalline.

The term “doxycycline composition” as used herein, includes an oraldoxycycline marketed under the brand name as ORACEA®-40 mg once dailycapsules—from Galderma Laboratories, approved by the US FDA with NDA No.050805 and indicated for the treatment of only inflammatory lesions(papules and pustules) of rosacea in adults. The doxycycline compositionincludes ORACEA® or its pharmaceutical equivalents or its therapeuticequivalents or later approved drugs which are designated as AB rated byUS FDA as per Approved Drug Products with Therapeutic EquivalenceEvaluations (34th edition) or drugs obtained marketing approval by USFDA through Abbreviated New Drug Application (ANDA) filing byestablishing bioequivalence.

The term “commercially available minocycline compositions” as usedherein, includes oral minocycline marketed under the brand name asSOLODYN®-45 mg once daily tablets—from Medicis Pharmaceutical Corp.,approved by the US FDA with NDA No. 050808 and indicated for thetreatment treat only inflammatory lesions of non-nodular moderate tosevere acne vulgaris in patients 12 years of age and older. Thecommercially available minocycline compositions includes SOLODYN® or itspharmaceutical equivalents or its therapeutic equivalents or laterapproved drugs which are designated as AB rated by US FDA as perApproved Drug Products with Therapeutic Equivalence Evaluations (34thedition) or drugs obtained marketing approval by US FDA throughAbbreviated New Drug Application (ANDA) filing by establishingbioequivalence.

The term “pharmaceutically acceptable salts” as used herein, includesthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like,which are well known in the art. The salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or separately by reacting the pharmaceutically activesubstance having a free base function with a suitable organic acid orinorganic acid. Examples of pharmaceutically acceptable salts include,but are not limited to, any of the salts or co-crystals of minocyclineselected from hydrochloride, hydrobromide, sulphate, citrate, phosphate,maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, andthe like. The salts may be in solvate, hydrate, hemihydrates, oranhydrous forms.

The term “therapeutically effective amount” as used herein, refers to aprescribed amount of minocycline, which is less than 45 mg. In someembodiments, the therapeutically effective amount of minocycline isabout 44 mg, about 43 mg, about 42 mg, about 41 mg, about 40 mg, about39 mg, about 38 mg, about 37 mg, about 36 mg, about 35 mg, about 34 mg,about 33 mg, about 32 mg, about 31 mg, about 30 mg, about 29 mg, about28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg,about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg,about 11 mg, or about 10 mg. Such therapeutically effective amountprovides a sufficient plasma and/or interstitial fluid concentration ofminocycline for treating an inflammatory skin condition. The specifiedamount of minocycline is expected to be low enough to avoid serious sideeffects. The effective amount of minocycline and duration of thetreatment will be based on the age and physical condition of the subjectbeing treated, the severity of the condition, the nature of concurrenttherapy, and like factors within the knowledge and expertise of theattending physician.

The term “reduced dose” refers to a dose of minocycline, wherein saiddose comprises less than 45 mg of minocycline. In some embodiments, saidreduced dose of minocycline comprises about 40 mg, about 35 mg, about 30mg, about 25 mg, about 20 mg, about 15mg or about 10 mg of minocycline.In some embodiments, the reduced dose of minocycline is about 44 mg,about 43 mg, about 42 mg, about 41 mg, about 40 mg, about 39 mg, about38 mg, about 37 mg, about 36 mg, about 35 mg, about 34 mg, about 33 mg,about 32 mg, about 31 mg, about 30 mg, about 29 mg, about 28 mg, about27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg,about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg,or about 10 mg of minocycline. The term “reduced dose” can also be usedherein to refer comparisons between minocycline and doxycycline. In thisregard, minocycline that is provided at a reduced dose as compared todoxycycline is of a reduced mg amount. For example, less than 40 mg ofminocycline is a reduced dose as compared to 40 mg doxycycline.Similarly, the term “equivalent dose” can be used to refer tocomparisons between minocycline and doxycycline. In this regard,minocycline that is provided at an equivalent dose as compared todoxycycline is of the same mg amount. For example, 40 mg of minocyclineis an equivalent dose to 40 mg doxycycline.

The term “sub-antimicrobial dose” refers to an amount having nosignificant antimicrobial effect on the body upon administration of suchamount.

The term, “inflammatory skin condition” as used herein, refers to acondition resulting in inflammatory lesions characterized by rosacea,acne, atopic dermatitis, folliculitis, perioral dermatitis,photo-damage, actinic keratosis, psoriasis, treatment of chronic wounds,bed sores, keratosis pilaris, scars including surgical and acne scars,sebaceous cysts, inflammatory dermatoses, post inflammatoryhyperpigmentation, xerosis, pruritis, lichen planus, nodular prurigo,eczema, or miliaria.

The term “rosacea” as used herein, includes a skin condition comprisinginflammatory lesions (papulopustular rosacea - papules, pustules andnodules), vascular instability and/or vascular ectasia(erythematotelangiectatic rosacea), edema, skin thickening and/orrhinophyma changes (phymatous rosacea), acne rosacea, or ocular changes(ocular rosacea), wherein the full scope of rosacea, including itscauses, symptoms, and effects as described by National Rosacea Society,which is a 501(c) (3) organization in the United States.

The term “acne” as used herein, includes a skin condition comprising allknown types of acne, for example, acne vulgaris, cystic acne, acneatrophica, bromide acne, chlorine acne, acne conglobata, acne cosmetica,acne detergicans, epidemic acne, acne estivalis, acne fulminans, halogenacne, acne indurata, iodide acne, acne keloid, acne mechanica, acnepapulosa, pomade acne, premenstrual acne, acne pustulosa, acnescorbutica, acne scrofulosorum, acne urticata, acne varioliformis, acnevenenata, propionic acne, acne excoriee, gram negative acne, steroidacne, and nodulocystic acne.

The term “subject” as used herein, refers to a human individual who mayor may not be suffering from an inflammatory skin condition, who is arecipient of an oral pharmaceutical composition described herein.

The term “patient” as used herein, refers to a human individual who issuffering from an inflammatory skin condition, who is a recipient of thean oral pharmaceutical composition described herein.

The term “efficacy” refers to a reduction or inhibition of severity ofan inflammatory skin condition such as rosacea, wherein said severity isassessed by counting inflammatory lesions, including papules, pustulesand/or nodules, before the onset of treatment; and counting inflammatorylesions after treatment has been initiated; and assessing changes in aninvestigator's global assessment (IGA) score and/or in the number ofinflammatory lesions. If desired, efficacy can be quantified byreduction of inflammatory lesion count from the baseline beforetreatment, by an improvement from the baseline in an IGA score, or byboth the reduction of inflammatory lesion count and the IGA score. Asused herein, the term “treatment success” can refer to a finding ofefficacy.

The term “equivalent efficacy” refers to comparative treatment using twodifferent compositions, wherein the resulting efficacy is substantiallythe same. For example, if treatment with two different compositions forthe same period of time results in substantially the same reduction inthe number of lesions, the compositions can be said to have equivalentor comparable efficacy.

The term “improved efficacy” refers to comparative treatment using twodifferent compositions, wherein the resulting efficacy of onecomposition is greater as compared to another composition. For example,if treatment with a first composition and a second composition for thesame period of time results in greater reduction in the number ofinflammatory lesions for the second composition as compared to the firstcomposition, the second composition is said to have improved efficacy ascompared to the first composition.

The term “substantially” can be used to modify a term or value such thatit is not an absolute. The term will be defined by the circumstances andthe terms that it modifies, as those terms are understood by thoseskilled in the art. The term is indicative of an approximation or someamount of deviation, rather than perfect and absolute. For example, aswill be recognized by those skilled in the art, when the term“substantially prevent” is used in connection with a prophylactictreatment, it should not be understood as an absolute term that wouldpreclude any sign of any skin condition in a subject. Rather, as used inthe context of prophylactic treatment, the term “substantially prevent”can refer to inhibiting the development of a skin condition, such as ina subject who may be predisposed to the skin condition but who has notyet been diagnosed as having it, limiting the severity of the developedskin condition, arresting the development of a skin condition, and thelike.

The term “An investigator's global assessment (IGA) score” as usedherein is determined by a trained medical professional evaluating theskin condition of a subject utilizing an investigative global assessmentof the skin condition. Typically, such global assessments assign a valueto the degree of rosacea exhibited by the skin. In addition to theassessment made by the medical professional, the subject's input andobservations of their skin condition and responses to various inquiries(e.g., stinging or burning sensations) also play a role in determiningthe IGA score that is assigned. For example, the IGA score for rosacea(Table 1) can range from 0 (clear) to 1 (almost clear) to 2 (mild) to 3(moderate) to 4 (severe).

TABLE 1 Grade Score Clinical description Clear 0 No inflammatory lesionspresent Almost clear 1 Very few small papules, pustules Mild 2 Few smallpapules pustules Moderate 3 Several Small or large papules, pustulesSevere 4 Numerous Small and/or large papules, pustules

The reduction in inflammatory lesion count is determined at each studyvisit inter alia by an absolute inflammatory lesion count or by apercentage change in inflammatory lesion count. The improvementassessment includes grading or scoring rosacea severity based on thetotal count or number of inflammatory lesions.

The term “moderate to severe rosacea” refers to at least about 10papulopustular lesions before treatment. For example, the subject canhave an IGA score of rosacea of about 3 or about 4, and at least about10, 12, 15, 20, 25 or more inflammatory papulopustular lesions beforetreatment. As used herein, a subject having “moderate rosacea” has anIGA score of rosacea of about 3. As used herein, a subject having“severe rosacea” has an IGA score of rosacea of about 4.

The term “interstitial fluid” as used herein refers to the extracellularfluid that is located outside blood vessels and in spaces between thetissue cells, and does not contain blood and blood cells, but maycontain non-cellular blood components.

The term “steady state” as used herein refers to a concentration levelof minocycline in which there is no further difference, or havingminimal difference, between the peak and trough concentrations ofminocycline, in plasma or interstitial fluid. Thus, at steady state, theplasma or interstitial fluid concentration level of minocycline does notsubstantially fluctuate within the dosing interval after repeated dosesof the formulation. The steady state is achieved in about 3 weeks orless, upon once or twice daily repeated dosing of the presentpharmaceutical composition comprising minocycline. In certain situationssteady state may be achieved in about 4 weeks.

The term “C_(maxP)” refers to the maximum plasma concentration.

The term “C_(maxIF)” refers to the maximum interstitial fluidconcentration.

The term “C_(minP)” refers to the minimum plasma concentration.

The term “C_(minIF)” refers to the minimum interstitial fluidconcentration.

The term “C_(maxSSP)” refers to the maximum plasma concentrationachieved at steady state.

The term “C_(maxSSIF)” refers to the maximum interstitial fluidconcentration achieved at steady state.

The term “CminSSP” refers to the minimum plasma concentration achievedat steady state.

The term “C_(minSSIF)” refers to the minimum interstitial fluidconcentration achieved at steady state.

The term “C_(maxP)/Dose” or “C_(maxP)/D” refers to the dose-normalizedmaximum plasma concentration.

The term “C_(maxIF)/Dose” or “C_(maxIF)/D” refers to the dose-normalizedmaximum interstitial fluid concentration.

The term “C_(maxSSP)/Dose” or “C_(maxSSP)/D” refers to thedose-normalized maximum plasma concentration achieved at steady state.

The term “C_(maxSSIF)/Dose” or “C_(maxSSIF)/D” refers to thedose-normalized maximum interstitial fluid concentration achieved atsteady state.

The term “C_(avgIF)” refers to the average concentration of minocyclinein plasma within a 24 hour dosing interval exhibited by administrationof the composition. C_(avgP) is calculated as,

$C_{avgP} = \frac{{AUC}_{0 - {tP}}\left( {{{AUC}\mspace{14mu} {over}\mspace{14mu} a\mspace{14mu} t} = {24\mspace{14mu} {hour}\mspace{14mu} {interval}\mspace{14mu} {in}\mspace{14mu} {plasma}}} \right)}{{Dosing}\mspace{14mu} {interval}\mspace{14mu} \left( {t = 24} \right)}$

The term “C_(avgIF)” refers to the average concentration of minocyclinein interstitial fluid within a 24 hour dosing interval exhibited byadministration of the composition. C_(avgIF) is calculated as,

$C_{avgIF} = \frac{{AUC}_{0 - {tIF}}\left( \mspace{14mu} \begin{matrix}{{{AUC}\mspace{14mu} {over}\mspace{14mu} a\mspace{14mu} t} = {24\mspace{14mu} {hour}\mspace{14mu} {interval}}} \\{{in}\mspace{14mu} {interstitial}\mspace{14mu} {fluid}}\end{matrix} \right)}{{Dosing}\mspace{14mu} {interval}\mspace{14mu} \left( {t = 24} \right)}$

The term “C_(avgSSP)” refers to the average concentration of minocyclinein plasma within a 24 hour dosing interval exhibited by administrationof the composition. C_(avgSS) is calculated as,

$C_{avgSSP} = \frac{{AUC}_{0 - {tSSP}}\begin{pmatrix}{{{AUC}\mspace{14mu} {over}\mspace{14mu} a\mspace{14mu} t} = {24\mspace{14mu} {hour}\mspace{14mu} {interval}}} \\{{at}\mspace{14mu} {steady}\mspace{14mu} {state}\mspace{14mu} {in}\mspace{14mu} {plasma}}\end{pmatrix}}{{Dosing}\mspace{14mu} {interval}\mspace{14mu} \left( {t = 24} \right)}$

The term “C_(avgSSIF)” refers to the average concentration ofminocycline in interstitial fluid within a 24 hour dosing intervalexhibited by administration of the composition. C_(avgSSIF) iscalculated as,

$C_{avgSSIF} = \frac{{AUC}_{0 - {tSSIF}}\begin{pmatrix}{{{AUC}\mspace{14mu} {over}\mspace{14mu} a\mspace{14mu} t} = {24\mspace{14mu} {hour}\mspace{14mu} {interval}}} \\{{at}\mspace{14mu} {steady}\mspace{14mu} {state}\mspace{14mu} {in}\mspace{14mu} {interstitial}\mspace{14mu} {fluid}}\end{pmatrix}}{{Dosing}\mspace{14mu} {interval}\mspace{14mu} \left( {t = 24} \right)}$

The term “AUC_(0-tP)” refers to the area under the plasmaconcentration-time curve; or minocycline exposure from time zero to timet, where “t” is the last sampling time point with measurable drugconcentration.

The term “AUC_(0-tIF)” refers to the area under the interstitial fluidconcentration-time curve; or minocycline exposure from time zero to timet, where “t” is the last sampling time point with measurable drugconcentration.

The term“AUC_(0-tSSP” refers to the area under the plasma concentration-time curve; or minocycline exposure from time zero to time t, where “t” is the last sampling time point with measurable drug concentration at steady state.)

The term “AUC_(-tSSIF)” refers to the area under the interstitial fluidconcentration-time curve; or minocycline exposure from time zero to timet, where “t” is the last sampling time point with measurable drugconcentration at steady state.

The term “AUC_(0-tP)/Dose” or “AUC_(0-tP)/D” refers to thedose-normalized area under the plasma concentration-time curve from timezero to time t, where “t” is the last sampling time point withmeasurable drug concentration.

The term “AUC_(0-fIF)/Dose” or “AUC_(0-tP)/D” refers to thedose-normalized area under the interstitial fluid concentration-timecurve from time zero to time t, where “t” is the last sampling timepoint with measurable drug concentration.

The term “AUC_(0-tSSP)/Dose” or “AUC_(0-tSS)/D” refers to thedose-normalized area under the plasma concentration-time curve from timezero to time t, where “t” is the last sampling time point withmeasurable drug concentration at steady state.

The term “AUC_(0-tSSIF)/Dose” or “AUC_(0-tSS)/D” refers to thedose-normalized area under the interstitial fluid concentration-timecurve from time zero to time t, where “t” is the last sampling timepoint with measurable drug concentration at steady state.

The term “coefficient of variation (CV)” refers to the ratio of standarddeviation to that of the mean value obtained from clinical data. Itshows the extent of variability in relation to the mean value of thestudy population. The CV is expressed as a percentage (%) and lower the% CV, more precise is the data.

The term “fluctuation index (FI_(p) or FI_(SSP))” or “degree offluctuation (DOF_(P))” refers a measurement of variation in drug plasmalevel upon administration, over the course of a dosing interval or atsteady state. The closer the fluctuation index to one, there is lessvariance over the course of a dosing period. Thus a reduced “FI_(P) orFI_(SSP)” signifies that the difference in peak and trough plasma levelshas been reduced. It is expressed as a ratio of maximum concentration tominimum concentration following administration according to therecommended dosing interval and calculated as,

Fluctuation index (FI_(P))=[C _(maxP) −C _(minP) ]/C _(avgP),

or

Fluctuation index (FI_(SSP))=[C _(maxSSP) −C _(minSSP) ]/C _(avgSSP)

The term “fluctuation index (FI_(IF) or FI_(SSIF))” or “degree offluctuation (DOF_(IF))” refers a measurement of variation in druginterstitial fluid level upon administration, over the course of adosing interval or at steady state. The closer the fluctuation index toone, there is less variance over the course of a dosing period. Thus areduced “FI_(IF) or FI_(SSIF)” signifies that the difference in peak andtrough interstitial fluid levels has been reduced. It is expressed as aratio of maximum concentration to minimum concentration followingadministration according to the recommended dosing interval andcalculated as,

Fluctuation index (FI_(IF))=[C _(maxIF) −C _(minP) ]/C _(avgIF),

or

Fluctuation index (FI_(SSIF))=[C _(maxSSIF) −C _(minSSIF) ]/C _(avgSSIF)

Oral tetracycline compounds are known for treating inflammatory skinconditions like rosacea. However, their higher doses and repeatedadministration with higher degree of fluctuation index or variationsbetween peak and trough plasma, affects the treatment regimen withhigher incidence of side effects. Having a treatment option with areduced dose, lesser fluctuation index or variance between peak andtrough plasma is long felt need.

The presently-disclosed invention is based, in part, on the surprisingdiscoveries disclosed herein. Unexpectedly, minocycline exhibitscomparative treatment results in % reduction in lesion counts forminocycline (about 40 mg), which is about 100% more as compared todoxycycline (40 mg) for equivalent doses. Additionally, % reduction inlesion counts for minocycline (about 20 mg) at a half dose is equivalentor greater than as compared to doxycycline (40 mg) at a whole dose.

Furthermore, as evidenced by comparative data, minocycline has improvedefficacy for treating rosacea as compared to doxycycline at anequivalent dose, and has equivalent efficacy at a half dose.

Accordingly, the present application relates to a method of treating aninflammatory skin condition with a reduced dose of minocycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition such as rosacea with a reduceddose of minocycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition such as acne with a reduced doseof minocycline.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition with a reduced dose ofminocycline to provide an equivalent or improved efficacy as compared toan oral doxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering an oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said administration results in an equivalent or improvedefficacy as compared to an oral doxycycline composition comprising 40 mgof doxycycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by selecting and administeringan oral pharmaceutical composition comprising an equivalent or a reduceddose of minocycline, as compared to an oral doxycycline compositioncomprising 40 mg of doxycycline, to a subject in need thereof.

In an embodiment, the present application relates to a method oftreating a rosacea by selecting and administering an oral pharmaceuticalcomposition comprising an equivalent or a reduced dose of minocycline,as compared to an oral doxycycline composition comprising 40 mg ofdoxycycline, to a subject in need thereof.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition in a subject which involves:

-   -   (a) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        ineffective, and administering an oral pharmaceutical        composition comprising an equivalent or a reduced dose of        minocycline; or    -   (b) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        effective, and administering an oral pharmaceutical composition        comprising a reduced dose of minocycline.

In an embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is ineffective, and administering anoral pharmaceutical composition comprising an equivalent or a reduceddose of minocycline.

In an embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is ineffective, and administering anoral pharmaceutical composition comprising an equivalent dose ofminocycline.

In an embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is ineffective, and administering anoral pharmaceutical composition comprising a reduced dose ofminocycline.

In another embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is effective, and administering an oralpharmaceutical composition comprising an equivalent or a reduced dose ofminocycline.

In another embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is effective, and administering an oralpharmaceutical composition comprising an equivalent dose of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea in a subject in need thereof, comprising selecting thesubject for whom treatment with an oral doxycycline compositioncomprising 40 mg of doxycycline is effective, and administering an oralpharmaceutical composition comprising a reduced dose of minocycline.

In yet another embodiment, the present application relates to a methodof treating rosacea in a subject in need thereof, comprising:

-   -   (a) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        ineffective, and administering an oral pharmaceutical        composition comprising an equivalent or a reduced dose of        minocycline; or    -   (b) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        effective, and administering an oral pharmaceutical composition        comprising an equivalent or a reduced dose of minocycline.

In an embodiment, the present application relates to a method ofpreparing an oral pharmaceutical composition for treating aninflammatory skin condition in a subject in need thereof, comprisingselecting and providing minocycline in said composition at an equivalentor reduced dose, as compared to an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method ofpreparing an oral pharmaceutical composition for treating rosacea in asubject in need thereof, comprising selecting and providing minocyclinein said composition at an equivalent or reduced dose, as compared to anoral doxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method ofpreparing an oral pharmaceutical composition for treating aninflammatory skin condition in a subject in need thereof, comprisingselecting and providing minocycline in said composition at an equivalentor reduced dose, as compared to an oral doxycycline compositioncomprising 40 mg of doxycycline, wherein said composition providesequivalent or improved efficacy as compared to the oral doxycyclinecomposition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method ofpreparing an oral pharmaceutical composition for treating rosacea in asubject in need thereof, comprising selecting and providing minocyclinein said composition at an equivalent or reduced dose, as compared to anoral doxycycline composition comprising 40 mg of doxycycline, whereinsaid composition provides equivalent or improved efficacy as compared tothe oral doxycycline composition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the pharmaceutical compositioncomprises less than 45 mg of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition comprises from about 10 mg to about 40 mg of minocycline.

In another aspect of the above embodiments, the method of preparing anoral pharmaceutical composition comprising minocycline, wherein saidcomposition comprises from about 10 mg to about 40 mg of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition comprises about 10 mg of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition comprises about 20 mg of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition comprises about 30 mg of minocycline.

In another aspect of the above embodiments, the pharmaceuticalcomposition comprises about 40 mg of minocycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering an oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said composition exhibits plasma concentration sufficient toreduce the severity of an inflammatory skin condition.

In an embodiment, the present application relates to a method oftreating rosacea by administering an oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said composition exhibits plasma concentration sufficient toreduce the severity of an inflammatory skin condition such as rosacea.

In an embodiment, the present application relates to a method oftreating rosacea by administering an oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said composition exhibits plasma concentration sufficient toreduce the severity of an inflammatory skin condition such as acne.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a reduced dose of minocycline toa subject in need thereof, wherein said composition exhibits a maximumplasma concentration (C_(maxP)) of not more than about 500 ng/ml ofminocycline upon administration, to reduce the severity of aninflammatory skin condition.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said composition exhibits a maximum plasmaconcentration (C_(maxP)) of not more than about 500 ng/ml of minocyclineupon administration, to reduce the severity of rosacea.

In an aspect of the above embodiments, the present application relatesto a method of treating acne by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said composition exhibits a maximum plasmaconcentration (C_(maxP)) of not more than about 500 ng/ml of minocyclineupon administration, to reduce the severity of acne.

In an aspect of the above embodiments, the present application relatesto a method of treating inflammatory skin condition by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said composition exhibits a maximumplasma concentration (C_(maxP)) of not more than about 500 ng/ml, about450 ng/ml, about 440 ng/ml or about 430 ng/ml of minocycline uponadministration, to reduce the severity of an inflammatory skincondition.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said composition exhibits a maximum plasmaconcentration (C_(maxP)) of not more than about 500 ng/ml, about 450ng/ml, or about 440 ng/ml or about 430 ng/ml of minocycline uponadministration, to reduce the severity of rosacea.

In an aspect of the above embodiments, the present application relatesto a method of treating acne by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said composition exhibits a maximum plasmaconcentration (C_(maxP)) of not more than about 500 ng/ml, about 450ng/ml, about 440 ng/ml or about 430 ng/ml of minocycline uponadministration, to reduce the severity of acne.

Oral tetracycline compounds are known for treating inflammatory skinconditions like rosacea. However, their higher doses and repeatedadministration with higher degree of fluctuation index or variationsbetween peak and trough plasma, affects the treatment regimen withhigher incidence of side effects. Having a treatment option with lesserfluctuation index or variance between peak and trough plasma is longfelt need.

Accordingly, the present application relates to a method of treating aninflammatory skin condition with lower fluctuation index, may be leadingto lesser incidence of side effects.

In one embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration exhibits a lower fluctuation index (FI_(p))[(C_(maxP)−C_(minP))/C_(avg)] in plasma.

In one embodiment, the present application relates to a method oftreating an rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration exhibits a substantially lower fluctuation index (FI_(P))[(C_(maxP)−C_(minP))/C_(avgP)] in plasma.

In one embodiment, the present application relates to a method oftreating an acne by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration exhibits a substantially lower fluctuation index (FI_(p))[(C_(maxP)−C_(minP))/C_(avgP)] in plasma.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration exhibits a lower fluctuation index (FI_(SSP))[(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration for about 3 weeks or less exhibits a lower(FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits a lower fluctuationindex (FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma.

In yet another embodiment, the present application relates to a methodof treating acne by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits a lower fluctuationindex (FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)].

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration for about 3 weeks or less exhibits a lowerfluctuation index (FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] inplasma, compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits a lower fluctuationindex (FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma,compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits at least about 30%lower fluctuation index (FI_(SSP)) [(C_(maxSSP)−C_(minSSP))/C_(avgSSP)]in plasma, compared to an oral doxycycline composition comprising 40 mgof doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of minocycline to a subject in need thereof, whereinsaid administration for at least 3 weeks or less exhibits at least about20%, about 15% or about 10% lower fluctuation index (FI_(SSP))[(C_(maxSSP)−C_(minSSP))/C_(avgSSP)] in plasma, compared to an oraldoxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition byadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of minocycline to a subject in need thereof, whereinsaid administration exhibits fluctuation index (FI_(SSP)) of about 0.9to about 1.3.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits fluctuation index (FI_(SSP)) of about 0.9 to about 1.3.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne by administering a pharmaceuticalcomposition comprising a therapeutically effective amount of minocyclineto a subject in need thereof, wherein said administration exhibitsfluctuation index of about (FI_(SSP)) 0.9 to about 1.3.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition byadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of minocycline to a subject in need thereof, whereinsaid administration exhibits fluctuation index (FI_(SSP)) of about 1.0.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits fluctuation index (FI_(SSP)) of about 1.0.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne by administering a pharmaceuticalcomposition comprising a therapeutically effective amount of minocyclineto a subject in need thereof, wherein said administration for about 3weeks or less exhibits fluctuation index (FI_(SSP)) of about 1.0 forabout 3.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits lower variation in maximum plasma concentration (C_(maxSSP))compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits lower variation in minocycline exposure (AUC_(0-tSSP)) inplasma compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits at least about 10% reduction in coefficient of variance (CV %)of maximum plasma concentration (C_(maxSSP)) compared to an oraldoxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits at least about 10%, about 15% or about 20% reduction incoefficient of variance (CV %) of maximum plasma concentration(C_(maxSSP)) compared to an oral doxycycline composition comprising 40mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits at least about 10% reduction in coefficient of variance (CV %)of minocycline exposure (AUC_(0-tSSP)) in plasma compared to an oraldoxycycline composition comprising 40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said administrationexhibits at least about 10%, about 15% or about 20% reduction incoefficient of variance (CV %) of minocycline exposure (AUC_(0-tSSP)) inplasma compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration for about 3 weeks or less maintains steadystate maximum plasma concentration (C_(maxSSP)) of minocycline.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein said compositionupon oral administration for about 3 weeks or less maintains steadystate maximum interstitial fluid concentration (C_(maxSSIF)) ofminocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less maintains steady state maximumplasma concentration (C_(maxSSP)) of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less maintains steady state maximuminterstitial fluid concentration (C_(maxSSIF)) of minocycline.

In another embodiment, the present application relates to a method oftreating acne by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less maintains steady state maximum plasma concentration(C_(maxSSP)) of minocycline.

In another embodiment, the present application relates to a method oftreating acne by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less maintains steady state maximum interstitial fluidconcentration (C_(maxSSIF)) of minocycline.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits plasma concentrationratio (C_(maxSSP):C_(maxP)) of at least about 0.9 to about 1.3.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a therapeutically effective amount of minocyclineto a subject in need thereof, wherein said administration exhibitsplasma concentration ratio (C_(maxSSP): C_(maxP)) of about 0.9.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less exhibits interstitial fluidconcentration ratio (C_(maxSSIP):C_(maxIF)) of at least about 0.7 toabout 1.4.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a therapeutically effective amount of minocyclineto a subject in need thereof, wherein said administration exhibitsinterstitial fluid concentration ratio (C_(maxSSIF):C_(maxIF)) of about1.0 for about 3 weeks or less of said administration.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidcomposition results in a desired steady state maximum plasmaconcentration (C_(maxSSP)) to treat the said inflammatory skincondition.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidcomposition results in a steady state maximum plasma concentration(C_(maxSSP)) of not more than about 500 ng/ml of minocycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidcomposition results in a desired steady state maximum interstitial fluidconcentration (C_(maxSSIF)) to treat the said inflammatory skincondition.

In another embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidcomposition results in a steady state maximum interstitial fluidconcentration (C_(maxSSIF)) of not more than about 200 ng/ml ofminocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition results in a steadystate maximum plasma concentration (C_(maxSSP)) of not more than about500 ng/ml of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein the said composition results in asteady state maximum plasma concentration (C_(maxSSP)) of not more thanabout 500 ng/ml, about 450 ng/ml, about 400 ng/ml, about 350 ng/ml orabout 300 ng/ml of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein the said composition results in asteady state maximum interstitial fluid concentration (C_(maxSSIF)) ofnot more than about 200 ng/ml of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein the said composition results in asteady state maximum interstitial fluid concentration (C_(maxSSIF)) ofnot more than about 200 ng/ml, about 180 ng/ml, about 170 ng/ml, about160 ng/ml or about 150 ng/ml of minocycline.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidadministration results in a desired maximum plasma concentration(C_(maxP)) on day 1 to treat the said inflammatory skin condition.

In one embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in amaximum plasma concentration (C_(maxP)) of not more than about 450 ng/mlof minocycline on day 1.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in amaximum plasma concentration (C_(maxP)) of not more than about 450ng/ml, about 440 ng/ml or about 430 ng/ml of minocycline on day 1.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising a therapeutically effective amountof minocycline to a subject in need thereof, wherein the saidadministration results in a desired maximum interstitial fluidconcentration (C_(maxIF)) on day 1 to treat the said inflammatory skincondition.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in amaximum interstitial fluid concentration (C_(maxIF)) of not more thanabout 150 ng/ml of minocycline on day 1.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in amaximum interstitial fluid concentration (C_(maxIF)) of not more thanabout 130 ng/ml, about 120 ng/ml or about 110 ng/ml of minocycline onday 1.

In an embodiment, the present application relates to a method oftreating inflammatory skin condition by administering a pharmaceuticalcomposition comprising a therapeutically effective amount of minocyclineto a subject in need thereof, wherein the said administration for about3 weeks or less maintains a desired plasma concentration of minocyclineto treat the said inflammatory skin condition.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less, maintains a desired plasmaconcentration of minocycline to treat said rosacea.

In an embodiment, the present application relates to a method oftreating acne by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, maintains a desired plasma concentration of minocyclineto treat said acne.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of minocycline to a subject in need thereof, whereinsaid composition upon oral administration for about 3 weeks or lessmaintains a constant plasma concentration of not more than about 500ng/ml to treat said rosacea.

In another aspect of the above embodiments, the method of treatingrosacea by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less maintains a constant plasma concentration of not more thanabout 500 ng/ml to treat said rosacea.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said composition upon oraladministration for about 3 weeks or less, maintains a desiredinterstitial fluid concentration of minocycline to treat said rosacea.

In another aspect of the above embodiments, the method of treatingrosacea by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, maintains a constant interstitial fluid concentration ofnot more than about 200 ng/ml of minocycline to treat said rosacea.

In another aspect of the above embodiments, the method of treatingrosacea by administering a pharmaceutical composition comprising atherapeutically effective amount of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, exhibits maximum interstitial fluid concentration(C_(maxSSIF)) of not more than about 200 ng/ml of minocycline to treatsaid rosacea.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results inminocycline exposure in plasma (AUC_(0-tp)) of not more than about 4080ng*hr/ml of minocycline on day 1.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results inminocycline exposure in interstitial fluid (AUC_(0-tIF)) of not morethan about 1625 ng*hr/ml of minocycline on day 1.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results inminocycline exposure in plasma at steady state (AUC_(0-tSSP)) of notmore than about 4550 ng*hr/ml of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results inminocycline exposure in interstitial fluid at steady state(AUC_(0-tSSIF)) of not more than about 1845 ng*hr/ml of minocycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in averageplasma concentration (C_(avgP)) of not more than about 215 ng/ml ofminocycline on day 1.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in averageinterstitial fluid concentration (C_(avgIF)) of not more than about 75ng/ml of minocycline on day 1.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in averageplasma concentration at steady state (C_(avgSSP)) of not more than about245 ng/ml of minocycline.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in averageinterstitial fluid concentration at steady state (C_(avgSSIF)) of notmore than about 90 ng/ml of minocycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tIF)/AUC_(0-tp)) of at least about 10%, about 20%, about 30%,about 40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of minocycline exposure in interstitial fluid toplasma (AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 10%, about 20%,about 30%, about 40% or about 50% higher as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 20 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration, exhibits ratio of minocycline exposure ininterstitial fluid to plasma (AUC_(0-tIF)/AUC_(0-tP)) of at least about35%, about 40%, about 45% or about 50%.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 20 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration for about 3 weeks or less, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 35%, about 40%, about 45%or about 50%.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tIF)/AUC_(0-tP)) of at least about 10%, about 20%, about 30%,about 40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of minocycline exposure in interstitial fluid toplasma (AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 10%, about 20%,about 30%, about 40% or about 50% higher as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 30 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration, exhibits ratio of minocycline exposure ininterstitial fluid to plasma (AUC_(0-tIF)/AUC_(0-tP)) of at least about35%, about 40%, about 45% or about 50%.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 30 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration for about 3 weeks or less, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 35%, about 40%, about 45%or about 50%.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tIF)/AUC_(0-tP)) of at least about 10%, about 20%, about 30%,about 40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of minocycline exposure in interstitial fluid toplasma (AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 10%, about 20%,about 30%, about 40% or about 50% higher as compared to oraladministration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 40 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration, exhibits ratio of minocycline exposure ininterstitial fluid to plasma (AUC_(0-tIF)/AUC_(0-tP)) of at least about35%, about 40%, about 45% or about 50%.

In an aspect of the above embodiments, the method of treating rosacea byadministering a pharmaceutical composition comprising about 40 mg ofminocycline to a subject in need thereof, wherein said composition uponoral administration for about 3 weeks or less, exhibits ratio ofminocycline exposure in interstitial fluid to plasma(AUC_(0-tSSIF)/AUC_(0-tSSP)) of at least about 35%, about 40%, about 45%or about 50%.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofaverage minocycline concentration in interstitial fluid to plasma or(C_(avgIF)/C_(avgP)) of at least about 10%, about 20%, about 30%, about40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma (C_(avgSSIF)/C_(avgSSP)) of at least about10%, about 20%, about 30%, about 40% or about 50% higher as compared tooral administration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 20 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration, exhibitsratio of average minocycline concentration in interstitial fluid toplasma or (C_(avgIF)/C_(avgP)) of at least about 30%, about 35%, about40% or about 45%.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 20 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma or (C_(avgSSIF)/C_(avgSSP)) of at leastabout 30%, about 35%, about 40% or about 45%.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofaverage minocycline concentration in interstitial fluid to plasma or(C_(avgIF)/C_(avgP)) of at least about 10%, about 20%, about 30%, about40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma (C_(avgSSIF)/C_(avgSSP)) of at least about10%, about 20%, about 30%, about 40% or about 50% higher as compared tooral administration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 30 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration, exhibitsratio of average minocycline concentration in interstitial fluid toplasma or (C_(avgIF)/C_(avgP)) of at least about 30%, about 35%, about40% or about 45%.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 30 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma or (C_(avgSSIF)/C_(avgSSP)) of at leastabout 30%, about 35%, about 40% or about 45%.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration, exhibits ratio ofaverage minocycline concentration in interstitial fluid to plasma or(C_(avgIF)/C_(avgP)) of at least about 10%, about 20%, about 30%, about40% or about 50% higher as compared to oral administration of adoxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said composition upon oral administration for about 3 weeks orless, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma (C_(avgSSIF)/C_(avgSSP)) of at least about10%, about 20%, about 30%, about 40% or about 50% higher as compared tooral administration of a doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 40 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration, exhibitsratio of average minocycline concentration in interstitial fluid toplasma or (C_(avgIF)/C_(avgP)) of at least about 30%, about 35%, about40% or about 45%.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 40 mg of minocycline to a subject in needthereof, wherein said composition upon oral administration for about 3weeks or less, exhibits ratio of average minocycline concentration ininterstitial fluid to plasma or (C_(avgSSIF)/C_(avgSSP)) of at leastabout 30%, about 35%, about 40% or about 45%.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition that comprisesadministering a pharmaceutical composition comprising a reduced dose ofminocycline to a subject in need thereof, wherein said reduced dosecomprises lower dose of minocycline compared to commercially availableminocycline compositions, including 50 mg, 75 mg, or 100 mg minocyclinecompositions.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises lower doseof minocycline compared to commercially available minocyclinecompositions, including 50 mg, 75 mg, or 100 mg minocyclinecompositions.

In an aspect of the above embodiments, the present application relatesto a method of treating acne that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises lower doseof minocycline compared to 50 mg, 75 mg or 100 mg minocyclinecompositions.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition that comprisesadministering a pharmaceutical composition comprising asub-antimicrobial dose of minocycline to a subject in need thereof.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea that comprises administering apharmaceutical composition comprising a sub-antimicrobial dose ofminocycline to a subject in need thereof.

In an aspect of the above embodiments, the present application relatesto a method of treating acne that comprises administering apharmaceutical composition comprising a sub-antimicrobial dose ofminocycline to a subject in need thereof.

In aspect of the above embodiments, the sub-antimicrobial dose ofminocycline is less than 45 mg. In another aspect, the sub-antimicrobialdose is less than about 40 mg. In another aspect, the sub-antimicrobialdose is less than about 30 mg. In another aspect, the sub-antimicrobialdose is less than about 20 mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition thatcomprises administering a pharmaceutical composition comprising areduced dose of minocycline to a subject in need thereof, wherein saidreduced dose comprises less than 45 mg dose of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises less than45 mg dose of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises less than45 mg dose of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition thatcomprises administering a pharmaceutical composition comprising areduced dose of minocycline to a subject in need thereof. In anembodiment, the reduced dose comprises less than 45 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating an inflammatory skin condition comprisesadministering a pharmaceutical composition comprising a reduced dose ofminocycline to a subject in need thereof, wherein said reduced dosecomprises about 40 mg; about 35 mg; about 30 mg; about 25 mg; about 20mg; about 15 mg; or about 10 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof. In an embodiment, the reduced dose comprisesless than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, lessthan 25 mg, less than 20 mg, less than 15 mg, or less than 10 mg. In anembodiment, the reduced dose comprises about 40 mg, about 35 mg, about30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg ofminocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof. In an embodiment, the reduced dose comprisesless than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, lessthan 25 mg, less than 20 mg, less than 15 mg, or less than 10 mg. In anembodiment, the reduced dose comprises about 40 mg, about 35 mg, about30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg ofminocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises about 10 mgto about 40 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises about 20 mgto about 40 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises about 20 mgof minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises about 30 mgof minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea that comprises administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises about 40 mgof minocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering an oral pharmaceuticalcomposition comprising about 20 mg of minocycline to a subject in needthereof, wherein said administration results in an equivalent efficacyas compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering an oralpharmaceutical composition comprising about 40 mg of minocycline to asubject in need thereof, wherein said administration results in improvedefficacy as compared to an oral doxycycline composition comprising 40 mgof doxycycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea in a subject in need thereof, comprisingselecting the subject for whom treatment with an oral doxycyclinecomposition comprising 40 mg of doxycycline is ineffective or effective,and administering an oral pharmaceutical composition comprising lessthan 45 mg of minocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea in a subject in need thereof, comprisingselecting the subject for whom treatment with an oral doxycyclinecomposition comprising 40 mg of doxycycline is ineffective or effective,and administering an oral pharmaceutical composition comprising about 10mg or about 40 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is ineffectiveor effective, and administering an oral pharmaceutical compositioncomprising about 20 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is ineffectiveor effective, and administering an oral pharmaceutical compositioncomprising about 30 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is ineffectiveor effective, and administering an oral pharmaceutical compositioncomprising about 40 mg of minocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea in a subject in need thereof, comprisingselecting the subject for whom treatment with an oral doxycyclinecomposition comprising 40 mg of doxycycline is ineffective or effective,and administering an oral pharmaceutical composition comprising lessthan 45 mg of minocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea in a subject in need thereof, comprisingselecting the subject for whom treatment with an oral doxycyclinecomposition comprising 40 mg of doxycycline is effective, andadministering an oral pharmaceutical composition comprising about 10 mgor about 40 mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is effective,and administering an oral pharmaceutical composition comprising about 20mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is effective,and administering an oral pharmaceutical composition comprising about 30mg of minocycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising selecting the subject for whom treatment with an oraldoxycycline composition comprising 40 mg of doxycycline is effective,and administering an oral pharmaceutical composition comprising lessthan about 40 mg of minocycline.

In yet another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising:

-   -   (a) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        ineffective, and administering an oral pharmaceutical        composition comprising about 20 mg, about 30 mg, or about 40 mg        of minocycline; or    -   (b) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        effective, and administering an oral pharmaceutical composition        comprising about 20 mg, about 30 mg, or less than about 40 mg of        minocycline.

In yet another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea in a subject in need thereof,comprising:

-   -   (c) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        ineffective, and administering an oral pharmaceutical        composition comprising about 20 mg, about 30 mg, or about 40 mg        of minocycline; or    -   (d) selecting the subject for whom treatment with an oral        doxycycline composition comprising 40 mg of doxycycline is        effective, and administering an oral pharmaceutical composition        comprising about 20 mg, about 30 mg, or about 40 mg of        minocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a reduced dose of minocycline toa subject in need thereof, wherein said reduced dose provides desiredplasma concentration of minocycline for treating the inflammatory skincondition.

In an aspect of the above embodiments, the present application relatesto a method of treating inflammatory lesions by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose provides desiredinterstitial fluid concentration of minocycline for treating saidinflammatory lesions.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose provides desiredplasma concentration of minocycline for treating said rosacea.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose provides desiredinterstitial fluid concentration of minocycline for treating saidrosacea.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said reduced dose provides desired plasmaconcentration of minocycline for treating said acne.

In another aspect of the above embodiments, the present applicationrelates to a method of treating acne by administering a pharmaceuticalcomposition comprising a reduced dose of minocycline to a subject inneed thereof, wherein said reduced dose provides sufficient interstitialfluid concentration of minocycline for treating said acne.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises less than45 mg dose of minocycline to provide a steady state maximum plasmaconcentration of not more than about 500 ng/ml of minocycline fortreating said rosacea.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising a reduced dose of minocycline to asubject in need thereof, wherein said reduced dose comprises less than45 mg dose of minocycline to provide a steady state maximum interstitialfluid concentration of not more than about 200 ng/ml of minocycline fortreating said rosacea.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea comprises administering a pharmaceuticalcomposition comprising about 10 mg to about 40 mg of minocycline to asubject in need thereof, wherein said administration to the subjectsresults in at least one of the following pharmacokinetic parameters whenmeasured in plasma samples on day 1:

-   (a) C_(maxP) of about 55 ng/ml to about 450 ng/ml;-   (b) AUC_(0-tP) of about 830 ng*hr/ml to about 4080 ng*hr/ml; or-   (c) C_(avgP) of about 30 ng/ml to about 215 ng/ml.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea comprises administering apharmaceutical composition comprising about 10 mg to about 40 mg ofminocycline to a subject in need thereof, wherein said administration tothe subjects results in at least one of the following pharmacokineticparameters when measured in interstitial fluid samples on day 1:

-   (a) C_(maxIF) of about 14 ng/ml to about 150 ng/ml;-   (b) AUC_(0-tIF) of about 250 ng*hr/ml to about 1625 ng*hr/ml; or-   (c) C_(avgIF) of about 5 ng/ml to about 75 ng/ml.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea comprises administering apharmaceutical composition comprising about 10 mg to about 40 mg ofminocycline to a subject in need thereof, wherein said administration tothe subjects results in at least one of the following steady statepharmacokinetic parameters when measured in plasma samples:

-   (a) C_(maXSSP) of about 70 ng/ml to about 440 ng/ml;-   (b) AUC_(0-tSSP) of about 830 ng*hr/ml to about 4550 ng*hr/ml; or-   (c) C_(avgSSP) of about 40 ng/ml to about 245 ng/ml.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea comprises administering apharmaceutical composition comprising about 10 mg to about 40 mg ofminocycline to a subject in need thereof, wherein said administration tothe subjects results in at least one of the following steady statepharmacokinetic parameters when measured in interstitial fluid samples:

-   (a) C_(maxSSIF) of about 15 ng/ml to about 150 ng/ml;-   (b) AUC_(0-tSSIF) of about 375 ng*hr/ml to about 1845 ng*hr/ml; or-   (c) C_(avgSSIF) of about 8 ng/ml to about 90 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in plasma samples on day 1:

-   (a) C_(maxP) of about 110 ng/ml to about 150 ng/ml;-   (b) AUC_(0-tP) of about 1210 ng*hr/ml to about 1625 ng*hr/ml; or-   (c) C_(avgP) of about 60 ng/ml to about 85 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in interstitial fluid sampleson day 1:

-   (a) C_(maxIF) of about 37 ng/ml to about 60 ng/ml;-   (b) AUC_(0-tIF) of about 500 ng*hr/ml to about 680 ng*hr/ml; or-   (c) C_(avgIF) of about 22 ng/ml to about 30 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in plasma samples:

-   (a) C_(maxSSP) of about 140 ng/ml to about 190 ng/ml;-   (b) AUC_(0-tSSP) of about 1660 ng*hr/ml to about 2245 ng*hr/ml; or-   (c) C_(avgSSP) of about 80 ng/ml to about 110 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in interstitialfluid samples:

-   (a) C_(maxSSIF) of about 52 ng/ml to about 70 ng/ml;-   (b) AUC_(0-tSSIF) of about 745 ng*hr/ml to about 1010 ng*hr/ml; or-   (c) C_(avgSSIF) of about 32 ng/ml to about 43 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in plasma samples on day 1:

-   (a) C_(maxP) of about 224 ng/ml to about 330 ng/ml;-   (b) AUC_(0-tP) of about 2215 ng*hr/ml to about 3107 ng*hr/ml; or-   (c) C_(avgP) of about 90 ng/ml to about 120 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in interstitial fluid sampleson day 1:

-   (a) C_(maxIF) of about 70 ng/ml to about 95 ng/ml;-   (b) AUC_(0-tIF) of about 900 ng*hr/ml to about 1215 ng*hr/ml; or-   (c) C_(avgIF) of about 40 ng/ml to about 50 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in plasma samples:

-   (a) C_(maxSSP) of about 215 ng/ml to about 290 ng/ml;-   (b) AUC_(0-tSSP) of about 2525 ng*hr/ml to about 3415 ng*hr/ml; or-   (c) C_(avgSSP) of about 140 ng/ml to about 180 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 30 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in interstitialfluid samples:

-   (a) C_(maxSSIF) of about 80 ng/ml to about 110 ng/ml;-   (b) AUC_(0-tSSIF) of about 1025 ng*hr/ml to about 1385 ng*hr/ml; or-   (c) C_(avgSSIF) of about 50 ng/ml to about 65 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in plasma samples on day 1:

-   (a) C_(maxP) of about 325 ng/ml to about 440 ng/ml;-   (b) AUC_(0-tP) of about 3115 ng*hr/ml to about 4080 ng*hr/ml; or-   (c) C_(avgP) of about 160 ng/ml to about 215 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingpharmacokinetic parameters when measured in interstitial fluid sampleson day 1:

-   (a) C_(maxIF) of about 95 ng/ml to about 150 ng/ml;-   (b) AUC_(0-iIF) of about 1200 ng*hr/ml to about 1625 ng*hr/ml; or-   (c) C_(avgIF) of about 55 ng/ml to about 75 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in plasma samples:

-   (a) C_(maxSSP) of about 285 ng/ml to about 410 ng/ml;-   (b) AUC_(0-tSSP) of about 3365 ng*hr/ml to about 4550 ng*hr/ml; or-   (c) C_(avgSSP) of about 175 ng/ml to about 245 ng/ml.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 40 mg of minocycline to a subject in need thereof,wherein said administration results in at least one of the followingsteady state pharmacokinetic parameters when measured in interstitialfluid samples:

-   (a) C_(maxSSIF) of about 105 ng/ml to about 145 ng/ml;-   (b) AUC_(0-tSSIF) of about 1365 ng*hr/ml to about 1845 ng*hr/ml; or-   (c) C_(avgSSIF) of about 65 ng/ml to about 90 ng/ml.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 40 mg of minocycline to a subject in needthereof, wherein said administration for about 3 weeks or less, exhibitsplasma concentration ratio (C_(maxSSP):C_(maxP)) of at least about 30%lower ratio compared to an oral doxycycline composition comprising 40 mgof doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline to asubject in need thereof, wherein said administration for about 3 weeksor less, exhibits plasma concentration ratio (C_(maxSSP):C_(maxP)) of atleast about 30%, about 35%, about 40%, about 45% or about 50% lowerratio compared to an oral doxycycline composition comprising 40 mg ofdoxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline to asubject in need thereof, wherein said administration for about 3 weeksor less, exhibits average plasma concentration (C_(maxSSP)) of at leastabout 20% lower compared to an oral doxycycline composition comprising40 mg of doxycycline.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline to asubject in need thereof, wherein said administration for about 3 weeksor less, exhibits average plasma concentration (C_(maxSSP)) of at leastabout 20%, about 25%, about 30%, about 35% or about 40% lower comparedto an oral doxycycline composition comprising 40 mg of doxycycline.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 10 mg to about 40 mg of minocycline, to a subject inneed thereof, upon oral administration exhibits at least one of thefollowing pharmacokinetic parameters, when measured in plasma samples:

-   (a) C_(max)/D of about 5 ng/ml/mg to about 11 ng/ml/mg; or-   (b) AUC_(0-t)/D of about 60 ng/ml/mg to about 102 ng/ml/mg.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 10 mg to about 40 mg of minocycline, to a subject inneed thereof, upon oral administration for about 3 weeks or lessexhibits at least one of the following pharmacokinetic parameters, whenmeasured in plasma samples :

-   (a) C_(maxSSP)/D of about 5 ng/ml/mg to about 12 ng/ml/mg; or-   (b) AUC_(0-tSSP)/D of about 60 ng/ml/mg to about 114 ng/ml/mg.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 20 mg of minocycline, to a subject in needthereof, upon oral administration exhibits at least one of the followingpharmacokinetic parameters, when measured in plasma samples:

-   (a) C_(maxP)/D of about 5.5 ng/ml/mg to about 7.5 ng/ml/mg; or-   (b) AUC_(0-tP)/D of about 60 ng/ml/mg to about 80 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 20 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in plasma samples:

-   (a) C_(maxSSP)/D of about 7 ng/ml/mg to about 9.5 ng/ml/mg; or-   (b) AUC_(0-tSSP)/D of about 80 ng/ml/mg to about 112 ng/ml/mg.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 30 mg of minocycline, to a subject in needthereof, upon oral administration exhibits at least one of the followingpharmacokinetic parameters, when measured in plasma samples:

-   (c) C_(maxP)/D of about 8.3 ng/ml/mg to about 10.8 ng/ml/mg; or-   (d) AUC_(0-tP)/D of about 75 ng/ml/mg to about 100 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 30 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in plasma samples:

-   (c) C_(maxSSP)/D of about 7 ng/ml/mg to about 9.5 ng/ml/mg; or-   (d) AUC_(0-tSSP)/D of about 85 ng/ml/mg to about 112 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline, to asubject in need thereof, upon oral administration exhibits at least oneof the following pharmacokinetic parameters, when measured in plasmasamples:

-   (a) C_(maxP)/D of about 8 ng/ml/mg to about 11 ng/ml/mg; or-   (b) AUC_(0-tP)/D of about 75 ng/ml/mg to about 102 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in plasma samples:

-   (a) C_(maxSSP)/D of about 7.2 ng/ml/mg to about 9.6 ng/ml/mg; or-   (b) AUC_(0-tSSP)/D of about 84 ng/ml/mg to about 114 ng/ml/mg.    -   C_(max)/D−10-40 mg interstitial fluid day 1 and steady state

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 10 mg to about 40 mg dose of minocycline, to a subjectin need thereof, upon oral administration exhibits at least one of thefollowing pharmacokinetic parameters, when measured in interstitialfluid samples:

-   (a) C_(maxIF)/D of about 1.8 ng/ml/mg to about 3 ng/ml/mg; or-   (b) AUC_(0-tIF)/D of about 25 ng/ml/mg to about 40 ng/ml/mg.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 10 mg to about 40 mg dose of minocycline, to a subjectin need thereof, upon oral administration for about 3 weeks or lessexhibits at least one of the following pharmacokinetic parameters, whenmeasured in interstitial fluid samples:

-   (a) C_(maxSSIF)/D of about 1.3 ng/ml/mg to about 3.6 ng/ml/mg; or-   (b) AUC_(0-tSSIF)/D of about 34 ng/ml/mg to about 46 ng/ml/mg.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 20 mg of minocycline, to a subject in needthereof, upon oral administration exhibits at least one of the followingpharmacokinetic parameters, when measured in interstitial fluid samples:

-   (a) C_(maxIF)/D of about 1.8 ng/ml/mg to about 2.4 ng/ml/mg; or-   (b) AUC_(0-tIF)/D of about 25 ng/ml/mg to about 34 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 20 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in interstitial fluid samples:

-   (a) C_(maxSSIF)/D of about 2.6 ng/ml/mg to about 3.5 ng/ml/mg; or-   (b) AUC_(0-tSSIF)/D of about 37 ng/ml/mg to about 50 ng/ml/mg.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 30 mg of minocycline, to a subject in needthereof, upon oral administration exhibits at least one of the followingpharmacokinetic parameters, when measured in interstitial fluid samples:

-   (c) C_(maxIF)/D of about 2.3 ng/ml/mg to about 3.0 ng/ml/mg; or-   (d) AUC_(0-tIF)/D of about 30 ng/ml/mg to about 40 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 30 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in interstitial fluid samples:

-   (c) C_(maxSSIF)/D of about 2.6 ng/ml/mg to about 3.5 ng/ml/mg; or-   (d) AUC_(0-tSSIF)/D of about 36 ng/ml/mg to about 44 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline, to asubject in need thereof, upon oral administration exhibits at least oneof the following pharmacokinetic parameters, when measured ininterstitial fluid samples:

-   (a) C_(maxIF)/D of about 2.3 ng/ml/mg to about 3.1 ng/ml/mg; or-   (b) AUC_(0-tIF)/D of about 30 ng/ml/mg to about 40 ng/ml/mg.

In another aspect of the above embodiments, the present applicationrelates to a method of treating rosacea by administering apharmaceutical composition comprising about 40 mg of minocycline, to asubject in need thereof, upon oral administration for about 3 weeks orless exhibits at least one of the following pharmacokinetic parameters,when measured in interstitial fluid samples:

-   (a) C_(maxSSIF)/D of about 2.6 ng/ml/mg to about 3.6 ng/ml/mg; or-   (b) AUC_(0-tSSIF)/D of about 34 ng/ml/mg to about 46 ng/ml/mg.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition or inflammatorylesions resulting from one or more of rosacea, acne vulgaris, atopicdermatitis, folliculitis, perioral dermatitis, photo-damage, actinickeratosis, psoriasis, treatment of chronic wounds, bed sores, keratosispilaris, scars including surgical and acne scars, sebaceous cysts,inflammatory dermatoses, post inflammatory hyperpigmentation, xerosis,pruritis, lichen planus, nodular prurigo, eczema, or miliaria.

In an aspect of the above embodiments, the method of treating rosacea byadministering an oral pharmaceutical composition comprising a reduceddose of minocycline to a subject in need thereof, wherein said rosaceais a papulopustular rosacea, acne rosacea, an erythematotelangiectaticrosacea, a phymatous rosacea, an ocular rosacea, an acne rosacea, apyoderma faciale, a rosacea conglobate, a mild rosacea, a moderaterosacea, a severe rosacea, a mild to moderate rosacea, or a moderate tosevere rosacea.

In an aspect of the above embodiments, the method of treating acne byadministering an oral pharmaceutical composition comprising a reduceddose of minocycline to a subject in need thereof, wherein said acne isacne vulgaris, cystic acne, acne atrophica, bromide acne, chlorine acne,acne conglobata, acne cosmetica, acne detergicans, epidemic acne, acneestivalis, acne fulminans, halogen acne, acne indurata, iodide acne,acne keloid, acne mechanica, acne papulosa, pomade acne, premenstrualacne, acne pustulosa, acne scorbutica, acne scrofulosorum, acneurticata, acne varioliformis, acne venenata, propionic acne, acneexcoriee, gram negative acne, steroid acne, and nodulocystic acne.

In another aspect of the above embodiments, the method of treatingrosacea by administering an oral pharmaceutical composition comprising areduced dose of minocycline to a subject in need thereof, wherein saidrosacea is characterized by inflammatory lesions.

In another aspect of the above embodiments, the method of treatingrosacea by administering an oral pharmaceutical composition comprising areduced dose of minocycline to a subject in need thereof, wherein saidrosacea is characterized by papules, pustules and/or nodules.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a therapeutic effective amountof less than 45 mg dose of minocycline to a subject in need thereof,wherein the inflammatory skin condition include rosacea.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a therapeutic effective amountof less than 45 mg dose of minocycline to a subject in need thereof,wherein the inflammatory skin condition is selected from the groupconsisting of a papulopustular rosacea an erythematotelangiectaticrosacea, a phymatous rosacea or an ocular rosacea, an acne rosacea, apyoderma faciale, a rosacea conglobate, a mild rosacea, a moderaterosacea, a severe rosacea, a mild to moderate rosacea, and a moderate tosevere rosacea.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a therapeutic effective amountof less than 45 mg dose of minocycline to a subject in need thereof,wherein the inflammatory skin condition includes acne.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduced the severity of rosacea as compared to theseverity of rosacea before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduced the severity of rosacea as compared to theseverity of rosacea before the treatment, and wherein said severity ofthe rosacea is assessed using IGA scale.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduces the IGA score compared to the IGA score before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduces the IGA score compared to the IGA score of placebocomposition.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the IGA score of the subject by at least one grade compared tothe IGA score before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the IGA score of the subject by at least one grade compared tothe IGA score of placebo composition.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the IGA score of the subject by at least one grade compared tothe IGA score about 1-16 weeks before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationresults in improved efficacy as assessed by the IGA score, in at leastabout 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%of the subjects as compared to the IGA score before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationresults in improved efficacy as assessed by the IGA score, in at leastabout 15% of the subjects as compared to the IGA score before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationresults in improved efficacy as assessed by the IGA score, in at leastabout 30% of the subjects as compared to the IGA score before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the IGA score of the subject by at least one grade compared tothe IGA score of an oral doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 10 mg to about 40 mg of minocycline, wherein saidadministration reduces the IGA score to an equal or greater extent ascompared to administration of an oral doxycycline composition comprising40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 20 mg of minocycline, wherein said administrationreduces the IGA score to an equal or greater extent as compared toadministration of an oral doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to 40 mg of minocycline, wherein saidadministration reduces the IGA score of the subject by at least about25%, about 50%, about 75% or about 100% compared to the IGA score of anoral doxycycline composition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to about 40 mg of minocycline, wherein saidadministration reduces the IGA score of the subject by at least about25% compared to the IGA score of an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the IGA score of the subject by at least about 25%, about 50%,about 75% or about 100% compared to the IGA score of an oral doxycyclinecomposition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the IGA score of the subject by at least about 25% compared tothe IGA score of an oral doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduced the severity of rosacea as compared to theseverity of rosacea before the treatment, and wherein said severity ofthe rosacea is assessed counting a number of inflammatory lesions.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduces the number of inflammatory lesions compared to theinflammatory lesions before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationsignificantly reduces the number of inflammatory lesions compared to theinflammatory lesions of placebo composition.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the number of inflammatory lesions of the subject by at leastabout 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95% or 100% as compared to the number of inflammatorylesions before the treatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the number of inflammatory lesions of the subject by at leastabout 15% as compared to the number of inflammatory lesions before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the number of inflammatory lesions of the subject by at leastabout 30% as compared to the number of inflammatory lesions before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering a reduced dose of minocycline, wherein said administrationreduces the number of inflammatory lesions of the subject by at leastabout 50% as compared to the number of inflammatory lesions before thetreatment.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 10 mg to about 40 mg of minocycline, wherein saidadministration significantly reduces the number of inflammatory lesionsscore to an equal or greater extent as compared to administration of anoral doxycycline composition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 20 mg of minocycline, wherein said administrationreduces the number of inflammatory lesions score to an equal or greaterextent as compared to administration of an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to about 40 mg of minocycline, wherein saidadministration reduces the inflammatory lesions by at least about 25%,about 50%, about 75% or about 100% compared to a number of inflammatorylesions of an oral doxycycline composition comprising 40 mg ofdoxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to about 40 mg of minocycline, wherein saidadministration reduces the inflammatory lesions by at least about 50%compared to a number of inflammatory lesions of an oral doxycyclinecomposition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to about 40 mg of minocycline, wherein saidadministration reduces the inflammatory lesions by at least about 75%compared to a number of inflammatory lesions of an oral doxycyclinecomposition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 30 mg to about 40 mg of minocycline, wherein saidadministration reduces the inflammatory lesions by at least about 100%compared to a number of inflammatory lesions of an oral doxycyclinecomposition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the inflammatory lesions by at least about 25%, about 50%, about75% or about 100% compared to a number of inflammatory lesions of anoral doxycycline composition comprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the inflammatory lesions by at least about 50% compared to anumber of inflammatory lesions of an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the inflammatory lesions by at least about 75% compared to anumber of inflammatory lesions of an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an aspect of the above embodiments, the method of treating rosacea byadministering about 40 mg of minocycline, wherein said administrationreduces the inflammatory lesions by at least about 100% compared to anumber of inflammatory lesions of an oral doxycycline compositioncomprising 40 mg of doxycycline.

In an aspect of the above embodiments, the present application relatesto a method of treating an inflammatory skin condition by administeringa pharmaceutical composition comprising a therapeutic effective amountof less than 45 mg dose of minocycline to a subject in need thereof,wherein said composition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a therapeutic effective amount of less than 45 mgdose of minocycline to a subject in need thereof, wherein saidcomposition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating acne by administering a pharmaceuticalcomposition comprising a therapeutic effective amount of less than 45 mgdose of minocycline to a subject in need thereof, wherein saidcomposition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 40 mg dose of minocycline to a subject inneed thereof, wherein said composition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 35 mg dose of minocycline to a subject inneed thereof, wherein said composition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 30 mg dose of minocycline to a subject inneed thereof, wherein said composition is administered orally.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising about 25 mg dose of minocycline to a subject inneed thereof, wherein said composition is administered orally.

In one embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 20 mg dose of minocycline to a subject in need thereof,wherein said composition is administered orally.

In one embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 15 mg dose of minocycline to a subject in need thereof,wherein said composition is administered orally.

In one embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising about 10 mg dose of minocycline to a subject in need thereof,wherein said composition is administered orally.

In an aspect of the above embodiments, the pharmaceutical composition ofpresent application is administered once daily.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutic effective amount of less than 45 mg dose ofminocycline to a subject in need thereof, wherein said composition isadministered once daily.

In an aspect of the above embodiments, the pharmaceutical composition ofpresent application is administered twice daily.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutic effective amount of less than 45 mg dose ofminocycline to a subject in need thereof, wherein said composition isadministered twice daily.

In another aspect of the above embodiments, the pharmaceuticalcomposition of present application is with or without food.

In another embodiments, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutic effective amount of less than 45 mg dose ofminocycline to a subject in need thereof, wherein said composition isadministered with or without food.

In an embodiment, the present application relates to a method oftreating rosacea by administering an oral pharmaceutical compositioncomprising a reduced dose of minocycline to a subject in need thereof,wherein said method provides body-weight-independent dosing regimen forminocycline.

In an aspect of the above embodiments, the present application relatesto a method of treating rosacea by administering a pharmaceuticalcomposition comprising a therapeutic effective amount of less than 45 mgdose of minocycline to a subject in need thereof, wherein saidcomposition is administered orally in the form of oral tablets,capsules, pills, minitablets, pellets, granules, powder, suspension,syrup and the like.

In an embodiment, the present application relates to a method oftreating an inflammatory skin condition by administering apharmaceutical composition comprising minocycline or a pharmaceuticallyacceptable salt thereof to a subject in need thereof, and measuringplasma concentration and/or interstitial fluid concentration ofminocycline in the subject.

As will be recognized by one of ordinary skill in the art, depending onthe circumstances, plasma concentration and/or interstitial fluidconcentration of minocycline can be measured daily, more than daily, orless than daily during an entire course of treatment or a portion of acourse of treatment of the subject. In some embodiments, for example,the subject can be measured for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, or 16 weeks.

In some embodiments, the method can involve monitoring measurementsuntil such time as a steady state maximum plasma and/or interstitialfluid concentration of minocycline in achieved and maintained for adefined period of time. In some embodiments, if a steady state ofminocycline in achieved and maintained for a defined period of time, thedose of minocycline can be maintained for the duration of the course oftreatment

In some embodiments, the method can involve identifying the steady statemaximum plasma concentration. In some embodiments, the method canfurther involve determining whether the steady state maximum plasmaconcentration is no greater than about 500 ng/ml.

As will be recognized by one of ordinary skill in the art, depending onthe circumstances, it can be beneficial to make use of plasmaconcentration and/or interstitial fluid concentration of minocycline todetermine a number of parameters. For example, in some embodiments, itcan be useful to calculate fluctuation index, as defined herein. In someembodiments, it can be useful to monitor fluctuation index. In someembodiments, it can be useful to determine whether the fluctuation indexis at about 1.0. In some embodiments, it can be useful to calculate anyvariation in fluctuation index from a first time point during treatmentto one or more additional time points during treatment. In someembodiments, it can be useful to determine whether variation in thefluctuation index is less than about 30, 20, or 10%.

In an embodiment, the present application relates to a pharmaceuticalcomposition comprising minocycline for treating an inflammatory skincondition in a subject in need thereof, wherein said composition is inthe form of oral tablets, capsules, pills, minitablets, pellets,granules, powder, suspension or syrup.

In an embodiment, the present application relates to a pharmaceuticalcomposition comprising minocycline for treating rosacea in a subject inneed thereof, wherein said composition is in the form of oral tablets,capsules, pills, minitablets, pellets, granules, powder, suspension orsyrup.

In an embodiment, the present application relates to a pharmaceuticalcomposition comprising minocycline for treating acne in a subject inneed thereof, wherein said composition is in the form of oral tablets,capsules, pills, minitablets, pellets, granules, powder, suspension orsyrup.

In an aspect of the above embodiment, the pharmaceutical composition ofminocycline is in the form of matrix-type compositions, whereinminocycline is distributed uniformly in the matrix of one or morepharmaceutically acceptable excipients.

In another aspect of the above embodiments, the pharmaceuticalcomposition of minocycline is in the form of gastro-retentive system,wherein said system is designed to retain in stomach for prolonged timeand release of minocycline to upper part of the gastrointestinal (GI)tract. Different approaches or systems to prolong the gastric residencetime include mucoadhesive or bioadhesive systems, high density systems,expandable or swelling systems, and floating drug delivery systems,including gas generating systems.

In yet another aspect of the above embodiments, the pharmaceuticalcomposition of minocycline is in the form of osmotic drug deliverysystem, wherein said system comprises minocycline layer with waterswellable polymer (osmogen) and a push layer.

In another aspect of the above embodiments, the pharmaceuticalcomposition of minocycline is in the form of modified releasecomposition, wherein said composition comprises an immediate release(IR) portion and/or an extended release (ER) portion containingminocycline with one or more pharmaceutically acceptable excipients.

In an embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises an immediate release (IR)portion and/or an extended release (ER) portion containing minocyclinewith one or more pharmaceutically acceptable excipients.

In an aspect of the above embodiments, the pharmaceutical composition ofpresent application comprises therapeutically effective amount ofminocycline to a subject in need thereof.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 0 to about 100percent of minocycline in an immediate release (IR) portion; (ii) about0 to about 100 percent minocycline in an extended release (ER) portion;and (iii) one or more pharmaceutically acceptable excipients.

In another embodiment, the present application relates to a method oftreating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 0 toabout 100 percent of minocycline in an immediate release (IR) portion;(ii) about 0 to about 100 percent minocycline in an extended release(ER) portion; and (iii) one or more pharmaceutically acceptableexcipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 0 to about 100percent of minocycline in an immediate release (IR) portion; (ii) about0 to about 100 percent minocycline in an extended release (ER) portion;and (iii) one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 30 percent ofminocycline in an immediate release (IR) portion; (ii) about 70 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 25 percent ofminocycline in an immediate release (IR) portion; (ii) about 75 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 20 percent ofminocycline in an immediate release (IR) portion; (ii) about 80 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 40 percent ofminocycline in an immediate release (IR) portion; (ii) about 60 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 50 percent ofminocycline in an immediate release (IR) portion; (ii) about 50 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 60 percent ofminocycline in an immediate release (IR) portion; (ii) about 40 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 70 percent ofminocycline in an immediate release (IR) portion; (ii) about 30 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 75 percent ofminocycline in an immediate release (IR) portion; (ii) about 25 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum plasma concentration of not more than about 500 ng/ml ofminocycline; and said composition comprises (i) about 80 percent ofminocycline in an immediate release (IR) portion; (ii) about 20 percentminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 0 toabout 100 percent of minocycline in an immediate release (IR) portion;(ii) about 0 to about 100 percent minocycline in an extended release(ER) portion; and (iii) one or more pharmaceutically acceptableexcipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 30percent of minocycline in an immediate release (IR) portion; (ii) about70 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 25percent of minocycline in an immediate release (IR) portion; (ii) about75 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 40percent of minocycline in an immediate release (IR) portion; (ii) about60 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 20percent of minocycline in an immediate release (IR) portion; (ii) about80 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 50percent of minocycline in an immediate release (IR) portion; (ii) about50 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 70percent of minocycline in an immediate release (IR) portion; (ii) about30 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 75percent of minocycline in an immediate release (IR) portion; (ii) about25 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 80percent of minocycline in an immediate release (IR) portion; (ii) about20 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating rosacea by administering a pharmaceutical compositioncomprising a therapeutically effective amount of minocycline to asubject in need thereof, wherein said administration results in a steadystate maximum interstitial fluid concentration of not more than about200 ng/ml of minocycline; and said composition comprises (i) about 60percent of minocycline in an immediate release (IR) portion; (ii) about40 percent minocycline in an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients

In an aspect of the above embodiments, the immediate release (IR) and/orextended release (ER) portions are present in the form of a granule,pellet, bead, spherule, mini tablet, powder and the like or mixturesthereof.

In an embodiment, the present application relates to a process ofpreparing pharmaceutical composition comprising a therapeuticallyeffective amount of minocycline.

In another embodiment, the present application relates to a process ofpreparing pharmaceutical composition comprising a therapeuticallyeffective amount of less than 45 mg dose of minocycline, wherein saidcomposition is administered orally.

In another aspect of the above embodiments, the process involvesconventional methods to prepare oral pharmaceutical composition, thatincludes, but not limited to, wet or dry granulation, using fluidizedbed granulator or high shear mixer granulator, direct compression,extrusion-spheronization, melt granulation/extrusion, spray-drying,spray-congealing, freeze-drying, or any other conventional process knownin the art.

In an aspect of the above embodiments, the process involves coating orlayering of minocycline over inert cores with coating or layeringmaterials comprising minocycline and/or other suitable pharmaceuticalexcipients like binders, plasticizers or disintegrants over the inertcores.

The process of coating or layering includes any method known in the artsuch as, but not limited to, by spraying a suspension or dispersion ofsaid coating material comprising minocycline, in a conventional coatingpan or fluidized bed equipment (such as a Wurster or Glatt) followed bydrying of cores. Alternatively, said coating materials may also beapplied by powder-coating, wherein the cores are maintained in a stickystate, a mixture of coating material is added continuously orperiodically so as to adhere to the sticky cores, followed by drying ofcoated cores when desired coating is achieved.

The “inert core” as used herein, refers to a pharmaceutically acceptableinert substrate which is routinely used in formulation art, thatincludes, but not limited to, powder or a multiparticulate such as agranule, a pellet, a bead, a spherule, a beadlet, a microcapsule, amillisphere, a nanocapsule, a nanosphere, a microsphere or a minitablet,which comprises at least one pharmaceutically acceptable excipientselected from the group comprising of water soluble, water insoluble,water swellable or water non swellable material such as starch, sugar,microcrystalline cellulose, vegetable gums, waxes, and the like.

The inert cores may also be prepared with the techniques known to aperson skilled in the art, such as, wet granulation, dry granulation, orextrusion-spheronization and the like. The inert cores have a size ofdiameter in the range of about 125 to about 600 microns.

Suitable solvent(s) used in the preparation of minocycline solution areselected from, but not limited to, water, methanol, ethanol, n-propanol,isopropanol, dichloromethane, acetone, absolute alcohol and the like ormixtures thereof.

Suitable examples of binder(s) that may be used in the presentapplication include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol, pre gelatinizedstarch, oxide such as polyethylene oxide and the like or mixturesthereof. The binders may be combination of two or more, such as hydroxypropyl cellulose and hydroxy propyl methyl cellulose. The binders usedin the present application have a viscosity from about 5 centipoise toabout 15 centipoise.

In another aspect of the above embodiments, the extended release (ER)portion are prepared by coating the immediate release (IR) portion withone or more release modifying polymers.

In another aspect of the above embodiments, the present applicationrelates to a process of preparing pharmaceutical composition ofminocycline comprising extended release (ER) portion, wherein the ERcoating layer has a thickness of not more than 200 μm.

Suitable examples of release modifying polymers that may be used in thepresent application include, but are not limited to, unsubstituted alkylcelluloses or cellulose ethers like ethyl cellulose; and substitutedalkyl celluloses or cellulose ethers like hydroxy alkyl celluloses andcarboxy alkyl celluloses such as hydroxy ethyl cellulose, hydroxy propylcellulose, hydroxy propyl methyl cellulose, carboxy methyl ethylcellulose and carboxy methyl cellulose; acrylic and methacrylic acidpolymers and copolymers such as methyl methacrylate, ethoxy ethylmethacrylates, ethyl acrylate, amino alkyl methacrylate copolymer,poly(acrylic acid), poly(methacrylic acid), polyacrylamide and glycidylmethacrylate copolymers; polyalkylene oxides such as polyethylene oxideand polypropylene oxide and copolymers of ethylene oxide and propyleneoxide; poly vinyl alcohols, gums, synthetic resins and the like ormixtures thereof. The release modifying polymers may be present inamounts ranging from about 5% to about 45% w/w of the composition.

In another embodiment, the pharmaceutical composition of minocycline ofpresent application may comprises one or more pharmaceuticallyacceptable excipient(s) selected from lubricants, glidants, anti-tackingagents, plasticizers, disintegrants or opacifying agents and the like ormixtures thereof.

The lubricant, glidant or anti-tacking agent may be used interchangeablyin the composition of the present application and are selected from, butnot limited to, metallic stearates such as magnesium stearate, calciumstearate, zinc stearate; stearic acid, hydrogenated vegetable oil,hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate,polyethylene glycols, corn starch, sodium stearyl fumarate, sodiumbenzoate, mineral oil, talc, colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, tribasic calcium phosphate andthe like or mixtures thereof. The amount of such agents may range fromabout 0.1% w/w to about 10%w/w of the composition.

The plasticizer used in the pharmaceutical composition of the presentapplication may be used in the coating layer to increase the flexibilityand strength of the coat/ layer, and suitable plasticizer may beselected from, but not limited to, propylene glycol, polyethyleneglycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate,dibutyl phthalate, dibutyl sebacate, tributyl citrate or mixturesthereof. The plasticizer may be present in amounts ranging from about0.1% to about 20% w/w of the composition.

The disintegrant used in the pharmaceutical composition of the presentapplication may be selected from, but not limited to, crospovidone,sodium starch glycolate, croscarmellose sodium, croscarmellosepotassium, croscarmellose calcium, carboxymethylcellulose,pregelatinized starch, carboxymethyl starch and the like or mixturesthereof. The disintegrant may be present in amount from 1% to 20% byweight of the composition.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising about 10 mg to about 40 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and/or ER portions with one or more pharmaceuticallyacceptable excipient(s); and (iv) filling the mixture of (iii) into acapsule or compressed into a tablet.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and/or ER portions with one or more pharmaceuticallyacceptable excipient(s); and (iv) filling the mixture of (iii) into acapsule or compressed into a tablet.

In an aspect of the above embodiments, the process comprises combiningthe IR and ER portions in a ratio of about 0:100, about 10:90, about20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30,about 75:25, about 80:20, about 90:10 or about 100:0.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and/or ER portions in a ratio of about 0:100 to about100:0 with one or more pharmaceutically acceptable excipient(s); and(iv) filling the mixture of (iii) into a capsule or compressed into atablet.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and ER portions in a ratio of about 20: 80 with one ormore pharmaceutically acceptable excipient(s); and (iv) filling themixture of (iii) into a capsule or compressed into a tablet.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and ER portions in a ratio of about 25: 75 with one ormore pharmaceutically acceptable excipient(s); and (iv) filling themixture of (iii) into a capsule or compressed into a tablet.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an immediate release (IR)portion; and/or (ii) preparing an extended release (ER) portion; (iii)combining the IR and ER portions in a ratio of about 30: 70 with one ormore pharmaceutically acceptable excipient(s); and (iv) filling themixture of (iii) into a capsule or compressed into a tablet.

In an aspect of the above embodiments, the present process of preparingpharmaceutical composition comprising less than 45 mg dose ofminocycline comprises steps of: (i) preparing an intragranular portion;and/or (ii) preparing an extragranular portion; (iii) mixing (i) and(ii) with suitable pharmaceutically acceptable excipients, (iv)compressing the mixture of (iii) into a tablet; and (v) optionallycoating tablet of (iv) using suitable coating material.

In an embodiment, the pharmaceutical composition comprising minocyclinecan also be co-administered (simultaneously or sequentially) with one ormore pharmaceutical agents of value in the form of commerciallyavailable dosage forms or which can be developed in a suitablepharmaceutically acceptable dosage forms for treating an inflammatoryskin condition or related disease conditions

In another embodiment, the pharmaceutical composition comprisingminocycline can be subjected to dissolution studies in 500 ml of pH 2.1simulated gastric fluid, pH 4.5 acetate buffer and pH 6.8 phosphatebuffer, with USP Type I apparatus at a speed of 100 rpm and 37° C. till3 hours.

Examples of the pharmaceutical agents that can be co-administered areselected from, but not limited to, systemic and topical antibiotics liketetracycline, minocycline, doxycycline, metronidazole, erythromycin andclindamycin; or retinoids like tretinoin (vitamin A or retinoic acid),isotretinoin (β-cis-retinoic acid), acitretin and the like or a mixturesthereof.

The present application is further illustrated by the examples which areprovided merely to be exemplary of the pharmaceutical compositiondescribed above and do not limit the scope of the application. Certainmodifications and equivalents will be apparent to those skilled in theart and are intended to be included within the scope of the presentapplication.

The present invention is illustrated below by reference to the followingexamples. However, one skilled in the art will appreciate that thespecific methods and results discussed are merely illustrative of thepresent invention, and not to be construed as limiting the application.The following examples may include compilations of data that arerepresentative of data gathered at various times during the course ofdevelopment and experimentation related to the present invention.

EXAMPLES Example 1-5

Pharmaceutical compositions were prepared including 40 mg, 30 mg, 20 mg,or 10 mg of minocycline. Further details regarding exemplarycompositions used for these non-limiting examples are set forth in Table1.

TABLE 1 (% w/w) Ex - 1 Ex - 2 Ex - 3 Ex - 4 Ex - 5 (eq. to (eq. to (eq.to (eq. to (eq. to Minocycline Minocycline Minocycline MinocyclineMinocycline Composition 40 mg) 30 mg) 20 mg) 10 mg) 40 mg) Drug loadingInert core 25.6 25.6 25.6 25.6 — Minocycline 24.9 24.9 24.9 24.9 24.9Hydrochloride Hydroxy propyl 10.4 10.4 10.4 10.4 — cellulose Hydroxypropyl methyl cellulose Microcrystalline — — — — 41.05 cellulosePolyethylene 1.3 1.3 1.3 1.3 — glycol 400 Talc 3.6 3.6 3.6 3.6 — WaterQuantity Quantity Quantity Quantity Quantity sufficient sufficientsufficient sufficient sufficient Barrier coating Hydroxy propyl 3.3 3.33.3 3.3 3.3 methyl cellulose Polyethylene 0.33 0.33 0.33 0.33 0.33glycol 400 Talc 0.98 0.98 0.98 0.98 0.98 Water Quantity QuantityQuantity Quantity Quantity sufficient sufficient sufficient sufficientsufficient Release modifying coating Ethyl cellulose 9.24 9.24 9.24 9.249.24 Hydroxy propyl 3.0 3.0 3.0 3.0 3.0 methyl cellulose Triethylcitrate 0.92 0.92 0.92 0.92 0.92 Talc 3.7 3.7 3.7 3.7 3.7 Isopropylalcohol Quantity Quantity Quantity Quantity Quantity sufficientsufficient sufficient sufficient sufficient Water Quantity QuantityQuantity Quantity Quantity sufficient sufficient sufficient sufficientsufficient Outer top coating Hydroxy propyl 7.48 7.48 7.48 7.48 7.48methyl cellulose Polyethylene 0.74 0.74 0.74 0.74 0.74 glycol 400 Talc2.24 2.24 2.24 2.24 2.24 Water Quantity Quantity Quantity QuantityQuantity sufficient sufficient sufficient sufficient sufficientLubrication Outer top 80.4 80.4 80.4 80.4 80.4 coated portions Barriercoated 17.6 17.6 17.6 17.6 17.6 portions Talc 1.96 1.96 1.96 1.96 1.96Total 100 100 100 100 100

Procedure:

Exemplary compositions can be prepared using the following procedure.

-   -   a. With regard to exemplary compositions 1-4, as set forth in        Table 1, a drug dispersion was prepared by mixing minocycline        hydrochloride, hydroxy propyl methyl cellulose, hydroxy propyl        cellulose, polyethylene glycol and talc in water and layered        onto inert core to obtain drug loaded pellets.    -   b. With regard to exemplary composition 5, as set forth in Table        1, drug and microcrystalline cellulose were wet granulated. The        wet mass was then extruded and the extrudates were spheronized        to prepare drug pellets.    -   c. A barrier coating solution was prepared by dissolving hydroxy        propyl methyl cellulose, followed by adding polyethylene glycol        and talc with stirring.    -   d. A release modifying coating solution was prepared by        dissolving the required amount of ethyl cellulose and hydroxy        propyl methyl cellulose in isopropyl alcohol, followed by adding        triethyl citrate.    -   e. An immediate release (IR) portion was prepared by coating the        barrier coating solution as prepared in step (c) onto a drug        loaded portion of step (a) or step (b).    -   f. An extended release (ER) portion was prepared by coating the        release modifying coating solution as prepared in step (d) onto        the drug loaded portion of step (a) or step (b), followed by an        outer top or seal coating.    -   g. A required quantity of the outer top coated portions and the        barrier coated portions were mixed with talc and filled into a        required size of empty hard gelatine capsule shells and packaged        in a suitable pharmaceutical storage bottle.

Example 6

An exemplary pharmaceutical composition comprising minocycline wasprepared as set forth in Table 2.

TABLE 2 Composition % w/w Drug loaded portion - 1 MinocyclineHydrochloride 5.3 (eq. to Minocycline 40 mg) Microcrystalline Cellulose10.6 Hydroxypropyl cellulose LF 0.3 Polyethylene Oxide 0.5 Crosscarmellose sodium 0.3 Sodium stearyl fumarate 0.001 Drug loaded releasemodifying and bio-adhesive portion - 2 Minocycline Hydrochloride 16.0Microcrystalline Cellulose 13.3 Hydroxypropyl methyl cellulose 13.3Polyethylene Oxide 39.9 Cross carmellose sodium 0.5 Sodium stearylfumarate 0.026 Total 100.0

Procedure:

Exemplary compositions can be prepared using the following procedure.

-   -   a. The noted amounts of minocycline hydrochloride,        microcrystalline cellulose, hydroxypropyl cellulose,        polyethylene oxide and cross carmellose sodium were sifted        through suitable sieve.    -   b. The blend of step (a) was lubricated using sodium stearyl        fumarate to prepare bioadhesive portion.    -   c. Required amount of minocycline hydrochloride,        microcrystalline cellulose, hydroxypropyl methyl cellulose,        polyethylene oxide and cross carmellose sodium were sifted        through suitable sieve.    -   d. The blend of step (c) was lubricated using sodium stearyl        fumarate to prepare release modifying portion.    -   e. The lubricated blend of step (b) was compressed on top of        drug loaded release modifying and bio-adhesive portion into        bi-layered tablets.

Example 7-8

Exemplary pharmaceutical compositions comprising minocycline weresprepared as set forth in Table 3.

TABLE 3 % w/w Composition Example - 7 Example - 8 Intragranular portionMinocycline Hydrochloride 10.3 28.1 (eq. to Minocycline 40 mg)Microcrystalline Cellulose 50.0 21.1 Polyethylene oxide — 17.6Hydroxypropyl methyl cellulose 26.9 7.0 Isopropyl alcohol: WaterQuantity Quantity sufficient sufficient Exragranular portionMicrocrystalline Cellulose 10.5 17.6 Colloidal Silicon Dioxide  0.8 1.1Sodium Stearyl Fumarate  1.5 1.1 Outer top coating Hydroxypropyl methylcellulose — 4.6 Talc — 1.4 Polyethylene Glycol — 0.5 Water — q.s. Total100   100

Procedure:

Exemplary compositions can be prepared using the following procedure.

-   -   a. Required amount of minocycline hydrochloride,        microcrystalline cellulose and/or polyethylene oxide were sifted        through suitable sieve.    -   b. Required amount of microcrystalline cellulose, colloidal        silicon dioxide and sodium stearyl fumarate were sifted through        suitable sieve.    -   c. Solution of hydroxypropyl methylcellulose was prepared in a        mixture of isopropyl alcohol and water.    -   d. The powder mass of step (a) was granulated with the solution        of step (c).    -   e. Granules of step (d) were dried in suitable dryer and dried        granules are passed through suitable sieve.    -   f. Example 7: Dried granules of step (e) were lubricated by        mixing with powder mass of step (b) and compressed into tablets.    -   g. Example 8: Dried granules of step (e) were lubricated by        mixing with powder mass of step (b) and compressed into tablets        followed by coating with outer top coating composition as        mentioned in Examples 1-5.

Example 9

The pharmacokinetic parameters for pharmaceutical compositions as shownin Examples 1 and 3 were studied by using an open-label, 6-cohortpharmacokinetic study. The study was conducted in total 24 healthy humansubjects in 6 groups, randomized to receive a single dose of compositionof examples 1 and 3; and ORACEA®-40 mg doxycycline capsules orally. Thesubjects were received the treatments at day 1, followed by sampling,and continued to self-administer it for next 19 days. At steady statelevel on day 21, the subjects were supervised for dosing followed bysampling and check-out 24 hours later. The sampling in plasma andinterstitial fluid is performed and the results are shown in followingtable 4, table 5, table 6, table 7 and table 8.

TABLE 4 (Plasma sample) Day 1 Day 21 Parameters Ex-1 Ex-3 ORACEA ® Ex-1Ex-3 ORACEA ® C_(max) (ng/ml) 382.83 130.68 405.86 337.74 164.46 701.85C_(min) (ng/ml) 3.29 4.01 5.2 96.96 35.11 38.96 C_(avg) (ng/ml) 187.4373.53 211 210.01 95.76 44.62 AUC_(0-t) 3549.64 1412.31 4377.52 3957.621953.92 6074.76 (ng*hr/ml) T_(max) (hr) 1.75 1.75 1.75 1.50 1.50 1.50

TABLE 5 (Fluctuation index at steady state in plasma sample) Day 21 Ex-1Ex-3 ORACEA ® Parameters Mean SD* % CV Mean SD % CV Mean SD % CV C_(max)(ng/ml) 337.74 95.45 28.26 164.46 70.87 43.09 701.85 534.2 76.11AUC_(0-t) 3957.62 1099 27.77 1953.92 645.8 33.05 6074.76 1980 32.59(ng*hr/ml) Fluctuation 1.15 1.35 1.51 index** *SD—Standard deviation**Fluctuation index - [(C_(max) − C_(min))/C_(avg)]

TABLE 6 (Variations in plasma sample) % Variations from day 1 to day 21Parameters Ex-1 Ex-3 ORACEA ® C_(max) (ng/ml) −12%  21% 42% AUC_(0-t)11% 28% 28% (ng*hr/ml) Fluctuation 14% 57% 59% index

TABLE 7 (Interstitial fluid sample) Day 1 Day 21 Parameters Ex-1 Ex-3ORACEA ® Ex-1 Ex-3 ORACEA ® C_(max) (ng/ml) 109.68 42.94 81.52 125.6960.64 114.69 C_(min) (ng/ml) 2.8 1.2 0.8 39.9 16.4 33.3 C_(avg) (ng/ml)63.6 26.3 49.5 76.9 37.1 26.6 AUC_(0-t) 1412.29 589.89 1088.55 1604.77877.82 1573.63 (ng*hr/ml) T_(max) (hr) 3.00 3.50 4.00 3.00 4.00 4.00

TABLE 8 (ratio of interstitial fluid to plasma samples) Interstitialfluid to plasma ratios (%) Ex-1 Ex-2 ORACEA ® Parameters Day 1 Day 21Day 1 Day 21 Day 1 Day 21 AUC_(0-t) 40 41 42 45 25 26 (ng*hr/ml) C_(avg)(ng/ml) 34 37 36 39 23 22

Example 10

The pharmaceutical compositions as shown in Example 1 and 3 were studiedin a 16-week, multi-center, randomized, double-blind, parallel-group,controlled study to evaluate efficacy. Subjects, who were at least 18years old, diagnosed with papulopustular rosacea were randomized to 4different treatment groups (50 subjects each in groups 1 to 4). Eachsubject was allocated to one of the treatment groups, receiving a singledose of Example 1 (Group 1) and Example 3 (Group 2); ORACEA®-40 mgdoxycycline capsules (Group 3); and placebo capsules (Group 4), orallyfor 16 weeks. Subjects' visits were scheduled at screening, baseline(day 1), and weeks 4, 8, 12 and 16.

Clinical assessments of efficacy was conducted based on, proportion ofsubjects with IGA ‘treatment success (reduction in IGA grade)’ andreduction in total inflammatory lesion count (sum of papules, pustules,and nodules) from baseline (day 1) to weeks 4, 8, 12 and 16. The resultsare shown in following table 9 (IGA ‘treatment success), table 10 (totalinflammatory lesion change), table 11 (P values) and FIG. 6, FIG. 7,FIG. 8.

TABLE 9 Subject IGA ‘treatment success’ population N (%) Example 1 35(66.04%) N = 53 Example 3 15 (31.91%) N = 47 ORACEA ® 16 (33.33%) N = 48Placebo 6 (11.54%) N = 52

TABLE 10 Papules change Pustules change Nodules change Totalinflammatory Subject in lesion no. in lesion no. in lesion no. lesionchange population (SD*) (SD*) (SD*) (SD) Example 1 −13.2 (7.94) −5.8(6.16) −0.2 (0.48) −19.2 (9.73) N = 53 Example 3 −8.6 (9.10) −4.0 (7.8)−0.1 (0.50) −12.7 (12.80) N = 47 ORACEA ® −7.3 (11.44) −3.0 (7.89) −0.1(0.62) −10.5 (15.20) N = 48 Placebo −3.1 (7.92) −4.3 (6.02) 0.2 (1.21)−7.2 (10.06) N = 52 *SD—Standard deviation %

TABLE 11 P values IGA ‘treatment Total inflammatory Parameters success’lesion change Example 1 vs. <0.0001 <0.0001 Placebo Example 3 vs. 0.01330.0246 Placebo Example 1 vs. 0.0010 0.0004 ORACEA ® Example 1 vs. 0.00070.0076 Example 3 Example 3 vs. 0.8828 0.3781 ORACEA ®

We claim:
 1. A method of treating rosacea in a subject in need thereof, comprising administering an oral pharmaceutical composition comprising a body-weight independent dose of about 10 mg to about 40 mg of minocycline to a subject in need thereof, wherein C_(max) in the subject's plasma is achieved at about 1.75 hours after administration and C_(maxSSP) of minocycline is not more than about 500 ng/ml, and wherein said rosacea is selected from papulopustular rosacea, erythematotelangiectatic rosacea, phymatous rosacea, ocular rosacea, pyoderma faciale, rosacea conglobate and combinations thereof.
 2. The method of claim 1, wherein the oral pharmaceutical composition is administered once daily.
 3. The method of claim 1, wherein the oral pharmaceutical composition comprises about 10 mg of minocycline.
 4. The method of claim 1, wherein the oral pharmaceutical composition comprises about 20 mg of minocycline.
 5. The method of claim 1, wherein the oral pharmaceutical composition comprises about 30 mg of minocycline.
 6. The method of claim 1, wherein the oral pharmaceutical composition comprises about 40 mg of minocycline.
 7. The method of claim 1, wherein said rosacea is a mild rosacea, a moderate rosacea, a severe rosacea, a mild to moderate rosacea, or a moderate to severe rosacea.
 8. The method of claim 1, further comprising selecting the subject for whom prior treatment with an oral doxycycline composition comprising 40 mg of doxycycline is effective or ineffective.
 9. The method of claim 8, further comprising selecting the subject for whom treatment with the oral doxycycline composition is ineffective, and administering the oral pharmaceutical comprising an equivalent dose or reduced dose of minocycline.
 10. The method of claim 8, further comprising selecting the subject for whom treatment with the oral doxycycline composition is effective, and administering the oral pharmaceutical composition comprising an equivalent dose or reduced dose of minocycline.
 11. The method of claim 8, further comprising administering the oral pharmaceutical composition comprising 40 mg of minocycline to the subject in need thereof, wherein said administration results in improved efficacy as compared to an oral doxycycline composition comprising 40 mg of doxycycline.
 12. The method of claim 8, further comprising administering the oral pharmaceutical composition comprising 20 mg of minocycline to the subject in need thereof, wherein said administration results in equivalent or improved efficacy as compared to an oral doxycycline composition comprising 40 mg of doxycycline.
 13. The method of claim 1, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75% of the subjects compared to the IGA score before the treatment.
 14. The method of claim 1, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 35% of the subjects compared to the IGA score before the treatment.
 15. The method of claim 1, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 45% of the subjects compared to the IGA score before the treatment.
 16. The method of claim 1, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 55% of the subjects compared to the IGA score before the treatment.
 17. The method of claim 6, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 25%, 50%, 75%, or 100% compared to the IGA score following administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 18. The method of claim 6, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 50% compared to the IGA score following administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 19. The method of claim 6, wherein the administration of the oral pharmaceutical composition results in improved efficacy as assessed by the IGA score by at least about 75% compared to the IGA score following administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 20. The method of claim 1, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions of the subject by at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95% or 100% as compared to the number of inflammatory lesions before the treatment.
 21. The method of claim 1, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions of the subject by at least about 45% as compared to the number of inflammatory lesions before the treatment.
 20. The method of claim 1, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions of the subject by at least about 50% as compared to the number of inflammatory lesions before the treatment.
 21. The method of claim 1, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions of the subject by at least about 60% as compared to the number of inflammatory lesions before the treatment.
 22. The method of claim 1, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions of the subject by at least about 70% as compared to the number of inflammatory lesions before the treatment.
 23. The method of claim 6, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions by at least about 15%, 30%, 50%, or 75% as compared to the number of inflammatory lesions reduced following the administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 24. The method of claim 6, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions by at least about 15% as compared to the number of inflammatory lesions reduced following the administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 25. The method of claim 6, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions by at least about 30% as compared to the number of inflammatory lesions reduced following the administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 26. The method of claim 6, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions by at least about 50% as compared to the number of inflammatory lesions reduced following the administration of an oral doxycycline composition comprising 40 mg of doxycycline.
 27. The method of claim 6, wherein the administration of the oral pharmaceutical composition reduces the number of inflammatory lesions by at least about 75% as compared to the number of inflammatory lesions reduced following the administration of an oral doxycycline composition comprising 40 mg of doxycycline. 